Abstract
Osteoporosis is a common comorbidity in end-stage liver disease (ESLD), yet its impact on waitlist survival remains underexplored, particularly in non-Western populations. This prospective cross-sectional study evaluated bone mineral density (BMD) and its association with mortality in 702 adult candidates, including 424 (60.4%) males and 278 (39.6%) females with an overall mean age of 45.13 ± 13.67 years, awaiting their first deceased-donor liver transplantation at a major referral center in Iran. BMD was assessed via dual-energy X-ray absorptiometry (DXA) at the lumbar spine, femoral neck, and total hip. Osteoporosis was present in 43.4% of patients, osteopenia in 36.9%, and only 19.7% had normal BMD. The mean Model for End-Stage Liver Disease (MELD) score was 18.1 ± 6.53. Patients with autoimmune hepatitis (AIH) exhibited the highest prevalence of osteoporosis (53.61%) among all etiologies. Multivariate Cox regression analysis revealed that osteoporosis was independently associated with increased waitlist mortality (HR = 1.90, 95% CI: 1.17–3.07). Conversely, primary sclerosing cholangitis (PSC) was associated with reduced mortality risk (HR = 0.42, 95% CI: 0.19–0.93). These findings underscore the high prevalence of bone disease in ESLD patients, identify AIH as a high-risk etiology for osteoporosis, and establish osteoporosis as a significant predictor of waitlist survival, highlighting the potential value of BMD assessment in pre-transplant risk stratification.
Keywords: Bone mineral density, Osteoporosis, End-stage liver disease, Liver transplantation, Waitlist mortality, Survival analysis
Subject terms: Endocrinology, Gastroenterology
Introduction
Liver transplantation has advanced significantly over the past 60 years. It is now the treatment of choice for most types of liver failure and hepatocellular carcinoma1–4; however, it is associated with complications, including those related to the bones5. Bone loss can begin as early as three months after transplantation, and up to 33% of patients with liver transplants may suffer fractures within the first year, significantly affecting the quality of life, morbidity, and even mortality6–9. Post-liver transplant bone loss and fracture risk are related to multiple risk factors, including immobility, malnutrition, muscle wasting, immunosuppressive therapy, corticosteroid use, etiology of liver disease, previous fractures, and the severity of preexisting bone disease before liver transplantation10–13.
In the past, the term “Hepatic Osteodystrophy” was used to describe bone diseases in patients with chronic liver disease, and it was mainly considered as osteoporosis, osteopenia, and rarely osteomalacia14,15. Currently, osteoporosis and osteopenia are the most common bone diseases in patients with chronic liver disease16. Osteoporosis is the most clinically important form of bone disease among chronic liver disease patients and transplant recipients, with incidence rates ranging between 11% and 58%17. There are several risk factors associated with osteoporosis in these patients, including low body mass index (BMI), advanced age, hypogonadism, estrogen deficiency, physical inactivity, corticosteroid use in patients with autoimmune disease, excessive alcohol consumption, smoking, vitamin D and calcium deficiency, previous fragility fractures, and genetic factors13.
Osteoporosis affects not only patients with cholestatic liver disease and cirrhosis but also those with chronic liver disease due to other underlying causes, even in the absence of cirrhosis. The primary cause of osteoporosis in cholestatic liver disease and cirrhosis is the reduction of bone formation, unlike post-menopausal osteoporosis, which results from increased bone resorption. Furthermore, chronic inflammation, direct toxic effects, or liver-related medications in other types of chronic liver disease can contribute to osteoporosis17. While much of the research on the link between bone disease and chronic liver disease has focused on cholestatic disease, there has been a lack of investigation into bone disease in patients with other prevalent chronic liver diseases, such as chronic viral hepatitis, Metabolic dysfunction-associated steatohepatitis, and other types18.
In addition, most existing studies have been conducted in Western populations, leaving a paucity of data from non-Western settings where genetic background, dietary patterns, and lifestyle factors may differ substantially15. The present study addresses this gap by evaluating a large, multi-etiology cohort of liver transplant candidates from a non-Western population. Beyond describing the burden of osteoporosis in this setting, we also sought to explore its potential impact on clinically meaningful outcomes. it is important to note that even among existing studies on bone health in liver disease, the majority have primarily focused on identifying risk factors for osteoporosis and its skeletal complications19. Only a limited number of investigations have examined the potential prognostic value of bone mineral density (BMD) in these patients20. Notably, the possible association between osteoporosis and mortality during the liver transplant waitlist period has been largely overlooked in literature.
In this study, our objective was to evaluate bone disease in patients with both cholestatic and other common chronic liver diseases in the middle eastern population. In addition, given the limited evidence on the prognostic role of osteoporosis in liver transplant candidates, we investigated whether osteoporosis is associated with waitlist survival, aiming to clarify its potential relevance for pretransplant risk assessment.
Methods and materials
Study design and participants
This prospective cross-sectional study was conducted among patients with end-stage liver disease (ESLD) who underwent pre-transplant referral for their first orthotopic liver transplantation in Abu-Ali Sina Hospital, the Middle East’s largest transplantation center, during May 2016 to September 2023. A total of 702 patients were included in the study. The study protocol was endorsed by the Shiraz University of Medical Sciences’ Ethics Committee and written informed consent was obtained from all subjects after a clear explanation of the study’s aim.
The study group consisted of all consecutive adult subjects who received dual-energy X-ray absorptiometry (DXA) for the determination of bone mineral density (BMD) at the first assessment for liver transplantation, prior to being placed on the official transplant waiting list. Patients with a history of bone metabolism disorders (e.g., renal impairment, defined as: increase in serum creatinine (SCr) by ≥ 0.3 mg/dL (26.5 µmol/L) within 48 h, or ≥ 50% increase in SCr from baseline within 7 days, or glomerular filtration rate (GFR) < 60 mL/min/1.73 m² for > 3 months21,22, parathyroid disease, immobilization for more than a few weeks), or previous exposure to hormone replacement therapy, bisphosphonates, calcitonin, anticonvulsants, or anticoagulants were excluded.
Following enrollment, patients were prospectively followed from the date of their BMD measurement until liver transplantation or death, as all participants reached one of these two outcomes during the study period.
At Abu-Ali Sina Hospital (Shiraz Transplant Center), all liver transplantations are performed exclusively using deceased donors, as living-donor liver transplantation is not part of the center’s standard allocation system. Therefore, all patients included in this study underwent deceased donor liver transplantation (DDLT), ensuring a uniform source of grafts and standardization of transplant procedures across the study cohort.
Clinical evaluations
Patients’ characteristics and osteoporosis risk factors, including age, weight, BMI, gender, menopausal status, history of fractures, etiology of liver disease, and medications associated with bone metabolism such as systemic glucocorticoids and Ca-D supplements were collected. The etiology of liver disease, including hepatitis B, hepatitis C, cryptogenic hepatitis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), Wilson disease, Alcoholic liver disease, Metabolic dysfunction-associated steatohepatitis (MASH), Budd-Chiari syndrome, and hepatocellular carcinoma (HCC), was confirmed in each patient through appropriate imaging and diagnostic methods, biochemical and serological markers, liver biopsy, and surgical evaluation of the explored liver in the patients who had undergone transplants. The Model for End-Stage Liver Disease (MELD) score was used to determine patients’ liver disease severity23,24. The score arose from the following equations: MELD = 3.78 [Ln Serum bilirubin (mg/dL)] + 11.2 [Ln INR] + 9.57 [Ln serum creatinine (mg/dL)] + 6.43, that Ln stands for the natural logarithm, and INR represents the International Normalized Ratio.
Bone densitometry
Areal bone mineral density (BMD) was assessed in the lumbar spine (L1-L4), left femoral neck, total hip, and whole body using dual-energy X-ray absorptiometry (DXA) (Hologic Corp, Bedford, MA, USA) according to the manufacturer and International Society for Clinical Densitometry (ISCD) protocols by a qualified technician. A phantom was used to standardize the densitometer before each measurement. The coefficient of variation was 1% or less for the lumbar spine, total hip, and whole body, and 1.8% for the femoral neck. The results were reported in grams per centimeter squared (g/cm2) and expressed as T-score and Z-score, which were calculated based on normal reference values of the age- and gender-matched group provided by the DXA system manufacturer25. Based on current recommendations for skeletally mature adults with a secondary cause of bone loss, osteoporosis was defined as a Z-score of -2 or lower or a T-score of -2.5 or lower, depending on the participants’ age25–28.
Statistical methods
Statistical Package for the Social Sciences version 22.0 (SPSS Inc., Chicago, IL, USA) was used to perform all statistical analyses. The mean and standard deviation were used to describe quantitative variables, while categorical variables were reported by frequency and percent. Cox proportional hazards regression analyses were performed to examine the association between potential predictors and waitlist mortality. Initially, univariate Cox regression models were fitted for each variable to assess crude associations with the outcome. Variables with a P-value < 0.20 in the univariate analysis, as well as those considered clinically relevant based on prior evidence29,30, were subsequently entered into a multivariate Cox regression model using a forward stepwise selection approach to identify independent predictors of mortality. Statistical significance in the multivariate model was defined as P < 0.05. The proportional hazards assumption was assessed for all models. Additionally, waitlist survival between groups was visualized using the Kaplan-Meier method and compared with the log-rank test.
Results
A total of 702 patients with an end-stage chronic liver disease listed for orthotopic liver transplantation were studied, including 424 (60.4%) males and 278 (39.6%) females, with a mean age of 46.05 ± 13.79 and 43.73 ± 13.39 years, respectively. The mean BMI for males was 24.92 ± 5.23, and for females, it was 25.38 ± 5.29. Among 278 females, 113 (40.65%) were post-menopausal, with a mean menopausal age of 46.04 ± 7.45 years. There were 13 (1.85%) patients with a history of fractures, 122 (17.37%) patients who had a history of glucocorticoid therapy for more than three months, and 24 (3.42%) patients who used Ca-D supplements. The mean MELD score for males and females was 18.63 ± 6.21 and 17.30 ± 6.91, respectively. During the study period, 69 (9.83%) subjects died from disease-associated causes. The etiology of liver disease in the studied subjects included hepatitis B (16.52%), hepatitis C (4.13%), cryptogenic hepatitis (9.12%), PBC (2.85%), PSC (19.66%), AIH (13.82%), Wilson disease (3.85%), Alcoholic liver disease (1.85%), MASH (20.23%), Budd-Chiari syndrome (2.99%), and HCC (5.13%), as shown in Table 1.
Table 1.
Characteristics and liver disease etiologies of the studied subjects.
| Variables | Total (702) | Males (424) | Females (278) |
|---|---|---|---|
| Weight (kg) | 69.85 (16.34) | 73.62 (16.71) | 64.1 (13.96) |
| Age (year) | 45.13 (13.67) | 46.05 (13.79) | 43.73 (13.39) |
| BMI (kg/m2) | 25.1 (5.26) | 24.92 (5.23) | 25.38 (5.29) |
| Diabetes mellitus | 125 (17.81) | 87 (20.52) | 38 (13.66) |
| MELD score | 18.1 (6.53) | 18.63 (6.21) | 17.3 (6.91) |
| Child-Pugh score | 8.66 (2.12) | 8.84 (2.03) | 8.33 (2.26) |
| Post-menopausal (Age at menopause, year) | 113 (40.65) | 0 (0) | 113 (40.65) |
| History of fracture (%) | 13 (1.85) | 9 (2.12) | 4 (1.44) |
| History of Calcium-D supplementation (%) | 24 (3.42) | 8 (1.89) | 16 (5.76) |
| Death (%) | 69 (9.83) | 40 (9.43) | 29 (10.43) |
| History of glucocorticoid therapy for more than 3 months (%) | 122 (17.37) | 48 (11.32) | 74 (26.52) |
| Hepatitis C (%) | 29 (4.13) | 26 (6.13) | 3 (1.08) |
| Hepatitis B (%) | 116 (16.52) | 86 (20.28) | 30 (10.79) |
| Cryptogenic hepatitis (%) | 64 (9.12) | 47 (11.08) | 17 (6.12) |
| Primary biliary cholangitis (%) | 20 (2.85) | 4 (0.94) | 16 (5.76) |
| Primary sclerosing cholangitis (%) | 138 (19.66) | 72 (16.98) | 66 (23.74) |
| Autoimmune hepatitis (%) | 97 (13.82) | 37 (8.73) | 60 (21.58) |
| Alcoholic liver disease (%) | 13 (1.85) | 13 (3.07) | 0 (0) |
| Wilson disease (%) | 27 (3.85) | 19 (4.48) | 8 (2.88) |
| Metabolic dysfunction-associated steatohepatitis (%) | 142 (20.23) | 88 (20.75) | 54 (19.42) |
| Budd-Chiari syndrome (%) | 21 (2.99) | 7 (1.65) | 14 (5.04) |
| Hepatocellular carcinoma (%) | 36 (5.13) | 28 (6.6) | 8 (2.88) |
| BUN (mg/dL) | 15.48 (5.2) | 15.56 (4.48) | 15.34 (6.16) |
| INR (ratio) | 1.83 (0.47) | 1.84 (0.51) | 1.8 (0.39) |
| Creatinine (mg/dL) | 1.04 (0.37) | 1.05 (0.39) | 1.02 (0.35) |
| Sodium (mEq/L) | 137.55 (2.72) | 137.42 (2.92) | 137.76 (2.38) |
| Albumin (g/dL) | 3.25 (0.33) | 3.23 (0.31) | 3.28 (0.36) |
| AST (U/L) | 84.09 (37.2) | 84.8 (42.68) | 82.98 (26.5) |
| ALT (U/L) | 60.06 (28.68) | 60.19 (32.05) | 59.85 (22.5) |
| Calcium (mg/dL) | 8.42 (0.66) | 8.35 (0.59) | 8.53 (0.79) |
| Phosphor (mg/dL) | 3.35 (1.38) | 3.65 (1.46) | 2.64 (0.92) |
| Platelet (×10^3/µL) | 118864.32 (51157.82) | 115728.48 (47979.91) | 123757.12 (55490.63) |
| Hemoglobin (g/dL) | 11.78 (1.15) | 11.83 (1.22) | 11.69 (1.03) |
| White blood cells | 6330.8 (1664.06) | 6324.02 (1774.45) | 6341.38 (1478.43) |
Abbr. BMI, Body mass index; MELD, Model for End-Stage Liver Disease.
The mean values of BMD in the lumbar spine, femoral neck, total hip, and whole body were 0.86 ± 0.15, 0.73 ± 0.14, 0.87 ± 0.15, and 1.04 ± 0.13 g/cm2, respectively. The prevalence of bone disease was 73.5% (33.33% osteopenia, 40.17% osteoporosis) in the lumbar spine, 58.83% (43.02% osteopenia, 15.81% osteoporosis) in the femoral neck, 43.44% (33.9% osteopenia, 9.54% osteoporosis) in the total hip, and 57.83% (36.18% osteopenia, 21.65% osteoporosis) in the whole body. The lowest T-score and Z-score were observed in the lumbar spine, with mean values of -1.96 ± 1.39 and − 1.47 ± 1.38, respectively, while the total hip had the highest T-score and Z-score, with mean values of -0.89 ± 1.06 and − 0.64 ± 1.04, respectively. Further BMD values, T-scores, Z-scores, and the prevalence of osteoporosis and osteopenia are listed in Table 2.
Table 2.
Bone mineral density values and the prevalence of bone diseases in the studied patients.
| BMD, lumbar spine (g/cm2) | Total (702) | Males (424) | Females (278) |
|---|---|---|---|
| 0.86 (0.15) | 0.88 (0.15) | 0.83 (0.15) | |
| T-score, lumbar spine (SD) | -1.96 (1.39) | -1.92 (1.41) | -2.03 (1.36) |
| Z-score, lumbar spine (SD) | -1.47 (1.38) | -1.53 (1.39) | -1.38 (1.35) |
| Osteoporosis, lumbar spine (n) | 282 (40.17) | 172 (40.57) | 110 (39.57) |
| Osteopenia, lumbar spine (n) | 234 (33.33) | 129 (30.42) | 105 (37.77) |
| BMD, femoral neck (g/cm2) | 0.73 (0.14) | 0.76 (0.14) | 0.69 (0.13) |
| T-score, femoral neck (SD) | -1.31 (1.1) | -1.21 (1.05) | -1.48 (1.15) |
| Z-score, femoral neck (SD) | -0.8 (1.12) | -0.68 (1.05) | -0.99 (1.19) |
| Osteoporosis, femoral neck (n) | 111 (15.81) | 48 (11.32) | 63 (22.66) |
| Osteopenia, femoral neck (n) | 302 (43.02) | 188 (44.34) | 114 (41.01) |
| BMD, total hip (g/cm2) | 0.87 (0.15) | 0.91 (0.15) | 0.81 (0.13) |
| T-score, total hip (SD) | -0.89 (1.06) | -0.76 (1.01) | -1.09 (1.11) |
| Z-score total hip (SD) | -0.64 (1.04) | -0.56 (0.99) | -0.74 (1.11) |
| Osteoporosis, total hip (n) | 67 (9.54) | 28 (6.6) | 39 (14.03) |
| Osteopenia, total hip (n) | 238 (33.9) | 133 (31.37) | 105 (37.77) |
| BMD, whole body (g/cm2) | 1.04 (0.13) | 1.06 (0.13) | 1 (0.12) |
| T-score, whole body (SD) | -1.39 (1.36) | -1.37 (1.31) | -1.42 (1.44) |
| Z-score, whole body (SD) | -1.1 (1.24) | -1.11 (1.22) | -1.09 (1.27) |
| Osteoporosis, whole body (n) | 152 (21.65) | 86 (20.28) | 66 (23.74) |
| Osteopenia, whole body (n) | 254 (36.18) | 164 (38.68) | 90 (32.37) |
Abbr. BMD, bone mineral density; SD, standard deviation.
The BMD of patients based on the etiology of the liver disease was expressed as T-scores and Z- scores in Table 3. The highest age and BMI were observed in patients with MASH, with a mean age of 54.46 ± 10.22 years and a mean BMI of 29.68 ± 5.42. The lowest BMD at the lumbar spine was found in patients with AIH, with a mean BMD of 0.82 ± 0.15; however, the lowest T-score in this area was seen in Wilson disease patients, with a mean value of -2.22 ± 1.14. Patients with PBC had the lowest BMD at the femoral neck (0.66 ± 0.08), expressed as a mean T-score of -1.73 ± 0.74. These patients also had the lowest BMD at the total hip, with a mean value of 0.81 ± 0.11. At the whole body, the lowest BMD (0.97 ± 0.13) and the lowest T-score (-2.06 ± 1.4) were noted in patients with Wilson’s disease. In addition, these patients had the lowest total hip T-score, with a mean value of -1.23 ± 0.9. Furthermore, patients with AIH had the highest prevalence of osteoporosis (53.61%) compared to those with other conditions.
Table 3.
Characteristics, values of bone mineral density, and prevalence of bone diseases among etiologic groups of liver diseases.
| Age (years) | Hepatitis B | Hepatitis C | Cryptogenic hepatitis | Primary biliary cholangitis | Primary sclerosing cholangitis | Autoimmune hepatitis | Wilson disease | Alcoholic liver disease | Metabolic dysfunction-associated steatohepatitis | Budd-Chiari syndrome | Hepatocellular carcinoma |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 53.21 (10.21) | 51.69 (8.45) | 47.69 (14.11) | 48.95 (10) | 39.78 (9.75) | 39.92 (13.05) | 27.41 (10.07) | 42.85 (11.26) | 54.46 (10.22) | 33.95 (10.57) | 50.08 (12.63) | |
| Weight (kg) | 71.47 (14.87) | 78.62 (11.82) | 66.53 (13.24) | 63.76 (12.74) | 62.84 (10.81) | 65.65 (15.04) | 63.98 (13.36) | 89.01 (20.65) | 82.85 (16.74) | 65.71 (12.52) | 69.91 (16.65) |
| BMI (kg/m2) | 25.46 (4.69) | 26.57 (3.7) | 23.8 (4.82) | 24.87 (4.8) | 22.53 (3.99) | 24.61 (5.11) | 22.49 (4.06) | 28.75 (6.46) | 29.68 (5.42) | 23.99 (3.14) | 24.78 (4.55) |
| BMD, lumbar spine (g/cm2) | 0.86 (0.15) | 0.85 (0.13) | 0.85 (0.14) | 0.84 (0.11) | 0.85 (0.14) | 0.82 (0.15) | 0.84 (0.12) | 0.96 (0.14) | 0.88 (0.17) | 0.88 (0.14) | 0.9 (0.17) |
| T-score, lumbar spine (SD) | -2.04 (1.36) | -2.09 (1.24) | -2.11 (1.25) | -1.94 (1.07) | -2.05 (1.35) | -2.18 (1.36) | -2.22 (1.14) | -1.2 (1.28) | -1.73 (1.5) | -1.64 (1.29) | -1.61 (1.5) |
| Z-score, lumbar spine (SD) | -1.47 (1.34) | -1.55 (1.5) | -1.61 (1.27) | -1.32 (0.85) | -1.79 (1.41) | -1.73 (1.3) | -1.73 (1.04) | -0.96 (1.23) | -0.92 (1.43) | -1.42 (1.34) | -1.14 (1.57) |
| BMD, femoral neck (g/cm2) | 0.74 (0.14) | 0.74 (0.12) | 0.73 (0.13) | 0.66 (0.08) | 0.72 (0.14) | 0.71 (0.13) | 0.72 (0.1) | 0.83 (0.18) | 0.76 (0.16) | 0.76 (0.21) | 0.75 (0.16) |
| T-score, femoral neck (SD) | -1.33 (1.07) | -1.35 (0.96) | -1.36 (0.96) | -1.73 (0.74) | -1.42 (1.15) | -1.43 (1.13) | -1.45 (0.79) | -0.76 (1.35) | -1.16 (1.18) | -1.17 (1.26) | -1.3 (1.17) |
| Z-score, femoral neck (SD) | -0.66 (1.07) | -0.69 (0.87) | -0.79 (0.92) | -1.21 (0.51) | -1.11 (1.17) | -1.08 (1.14) | -1.31 (0.69) | -0.33 (1.33) | -0.38 (1.1) | -0.78 (1.69) | -0.69 (1.24) |
| BMD, total hip (g/cm2) | 0.89 (0.15) | 0.88 (0.13) | 0.88 (0.14) | 0.81 (0.11) | 0.82 (0.15) | 0.83 (0.14) | 0.83 (0.13) | 0.97 (0.18) | 0.92 (0.16) | 0.86 (0.14) | 0.91 (0.17) |
| T-score, total hip (SD) | -0.83 (0.96) | -0.87 (1.02) | -0.81 (1.03) | -1.21 (0.94) | -1.2 (1.1) | -1.09 (1.1) | -1.23 (0.9) | -0.42 (1.18) | -0.6 (1.06) | -0.99 (1.01) | -0.75 (1.2) |
| Z-score total hip (SD) | -0.48 (0.97) | -0.61 (0.96) | -0.62 (0.91) | -0.84 (0.69) | -1.04 (1.09) | -0.91 (1.05) | -1.15 (0.88) | -0.23 (1.16) | -0.16 (0.98) | -0.79 (1.05) | -0.5 (1.16) |
| BMD, whole body (g/cm2) | 1.04 (0.12) | 1.04 (0.14) | 1.03 (0.13) | 1.03 (0.1) | 1.03 (0.12) | 1 (0.13) | 0.97 (0.13) | 1.13 (0.1) | 1.06 (0.13) | 1.05 (0.13) | 1.06 (0.14) |
| T-score, whole body (SD) | -1.42 (1.15) | -1.46 (1.35) | -1.57 (1.29) | -1.18 (0.99) | -1.39 (1.28) | -1.54 (1.46) | -2.06 (1.4) | -0.71 (1.02) | -1.15 (1.35) | -1 (1.43) | -1.24 (1.41) |
| Osteoporosis (n) | 49 (42.24) | 13 (44.83) | 30 (46.88) | 9 (45) | 67 (48.55) | 52 (53.61) | 11 (40.74) | 4 (30.77) | 54 (38.03) | 11 (52.38) | 14 (38.89) |
| Osteopenia (n) | 47 (40.52) | 12 (41.38) | 25 (39.06) | 9 (45) | 48 (34.78) | 30 (30.93) | 10 (37.04) | 1 (7.69) | 53 (37.32) | 3 (14.29) | 11 (30.56) |
Abbr. BMI, Body mass index; BMD, bone mineral density; SD, standard deviation.
In the multivariate Cox regression analysis, osteoporosis emerged as an independent predictor of increased waitlist mortality among patients with chronic liver disease awaiting liver transplantation (HR = 1.90, 95% CI: 1.17–3.07, P = 0.008). Conversely, primary sclerosing cholangitis (PSC) was associated with a significantly lower risk of death while on the waitlist (HR = 0.42, 95% CI: 0.19–0.93, P = 0.033). No other demographic, clinical, or etiological variables demonstrated a statistically significant association with waitlist survival in the adjusted model. The complete results of univariate and multivariate Cox regression analyses are presented in Table 4.
Table 4.
Cox regression analysis of the risk factors for the survival of the included cases.
| Variable | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| P-Value | Hazard Ratio (95% CI) | P-Value | Hazard Ratio (95% CI) | |
| Age | 0.152 | 1.013 (0.995–1.032) | ||
| BMI | 0.911 | 0.997 (0.953–1.044) | ||
| MELD | 0.563 | 1.011 (0.975–1.048) | ||
| Sex | 0.655 | 1.115 (0.691–1.798) | ||
| History of Fracture | 0.792 | 0.767 (0.106–5.524) | ||
| History of Calcium-D supplement | 0.35 | 0.390 (0.054–2.808) | ||
| History of glucocorticoid therapy | 0.241 | 0.047 (0.000–7.835) | ||
| Hepatitis B | 0.61 | 1.170 (0.640–2.140) | ||
| Hepatitis C | 0.446 | 1.481 (0.540–4.065) | ||
| Cryptogenic hepatitis | 0.422 | 1.353 (0.647–2.826) | ||
| Primary biliary cholangitis | 0.334 | 0.048 (0.000–23.060) | ||
| Primary sclerosing cholangitis | 0.042 | 0.445 (0.204–0.972) | 0.033 | 0.42 (0.19_0.93) |
| Autoimmune hepatitis | 0.583 | 1.198 (0.629–2.282) | ||
| Wilson disease | 0.802 | 1.160 (0.365–3.688) | ||
| Alcoholic liver disease | 0.82 | 0.795 (0.110–5.729) | ||
| Metabolic dysfunction-associated steatohepatitis | 0.549 | 1.187 (0.678–2.076) | ||
| Budd-Chiari syndrome | 0.46 | 1.547 (0.486–4.920) | ||
| Hepatocellular carcinoma | 0.759 | 0.834 (0.262–2.654) | ||
| Osteoporosis | 0.012 | 1.849 (1.146–2.983) | 0.008 | 1.90 (1.17_3.07) |
Abbr. BMI, Body mass index; MELD, Model for End-Stage Liver Disease.
To further visualize the impact of osteoporosis on waitlist survival, we performed a Kaplan-Meier survival analysis and compared the curves using the log-rank test. As shown in [Figure 1], patients with osteoporosis had a significantly lower probability of survival while on the waitlist compared to those without osteoporosis (Log-rank test: χ² = 8.122, P = 0.004).
Fig. 1.
Kaplan-Meier survival curves for liver transplant waitlist candidates stratified by osteoporosis status. Patients diagnosed with osteoporosis (red line) had a significantly lower probability of survival while on the transplant waitlist compared to patients without osteoporosis (blue line) (Log-rank test, χ² = 8.122, P = 0.004).
Discussion
Our study provides a comprehensive evaluation of bone mineral density in a large, non-Western cohort of liver transplant candidates with varied etiologies. By linking low BMD to waitlist mortality, we highlight the importance of bone health not only as a comorbidity but as a potential independent predictor of survival in chronic liver disease.
Liver transplantation remains a life-saving intervention for patients with end-stage liver disease, yet it is accompanied by a spectrum of systemic complications, among which bone disease is increasingly recognized as a major concern. Despite the clinical relevance of osteoporosis in this population, bone health has traditionally received less attention in pre-transplant evaluations compared to hepatic and renal parameters. Moreover, most existing studies have focused on Western populations or specific liver disease subtypes, leaving gaps in our understanding of bone disease burden and its prognostic implications in more diverse cohorts15.
In this study, BMD values met the definitions for osteoporosis in 43.4%, osteopenia in 36.9%, and only 19.47% of the patients had normal BMD values at the lumbar spine, femoral neck, and total hip. This high prevalence of osteoporosis aligns with previous studies indicating a substantial prevalence of osteoporosis among patients with end-stage liver disease, particularly those waiting for liver transplantation. This finding is particularly noteworthy given the demographic characteristics of our cohort, which consisted of a non-Western population with a wide range of underlying liver disease etiologies, including viral hepatitis, autoimmune hepatitis, alcohol-related liver disease, and MASH. Despite these differences, the prevalence of osteoporosis observed in our study closely mirrors that reported in Western cohorts, suggesting that bone loss in end-stage liver disease may be a universal phenomenon, independent of geographic or etiological variation. These findings reinforce the external validity of our results and underscore the importance of early bone health assessment across diverse transplant populations11,31–34.
In this study, the prevalence of osteoporosis was also reported according to the etiology of liver disease. The results indicated that patients with AIH exhibited the highest rates of osteoporosis compared to other conditions. Patients with AIH are under glucocorticoid therapy, which can lead to rapid bone loss initially and a low turnover state in the long term due to an early and transient increase in bone resorption and a long-standing decrease in bone formation35. Nonetheless, the prevalence of different etiologies varies across studies9,15,36–39. This variation could be attributed to differences in the sample sizes and characteristics of the studied populations, as well as differing definitions of osteoporosis, the measurement sites of BMD, and the severity of liver disease.
This study found a statistically significant association between osteoporosis and mortality in patients with chronic liver disease awaiting transplantation. Patients diagnosed with osteoporosis exhibited inferior survival during the waiting period, suggesting that low bone mineral density may serve as an independent predictor of adverse outcomes in this population. While traditional risk stratification models often emphasize hepatic function and systemic complications, our findings highlight the prognostic value of bone health itself. Osteoporosis may reflect underlying frailty, reduced physiological reserve, and increased vulnerability to infections and immobility-related complications—all of which can contribute to mortality. These results are consistent with previous studies showing that low BMD and fragility fractures are associated with increased short-term mortality and post-transplant complications in liver transplant candidates and other solid organ recipients39–42. Beyond its skeletal implications, osteoporosis in chronic liver disease represents a multidimensional systemic vulnerability. The linkage between low BMD and poor outcomes is orchestrated by a complex interplay of immune dysfunction, chronic inflammation, oxidative stress, endocrine and metabolic disturbances, and musculoskeletal decline15,43,44. Frailty and sarcopenia—closely associated with osteoporosis—further compromise physiological reserve and increase susceptibility to infection, immobility, and prolonged hospitalization44–46. Given these multifactorial risks, the presence of osteoporosis and its sequelae in chronic liver disease should prompt early screening, risk stratification via opportunistic imaging, and timely initiation of nutritional, metabolic, anti-resorptive, and rehabilitation-based therapeutics. Integration of bone health parameters into transplant evaluation algorithms—alongside conventional hepatic scores—may optimize candidate selection, guide perioperative interventions, and ultimately enhance survival and quality of life in this high-risk cohort. Recognizing osteoporosis as more than a comorbidity, but rather a dynamic surrogate of systemic disease severity, frailty, and immune dysfunction, should fundamentally inform both clinical research design and multidisciplinary management approaches in the care of patients with chronic liver disease awaiting transplantation. Future investigations with higher levels of evidence, including large-scale prospective cohorts and randomized controlled trials, are warranted to validate these strategies and to establish standardized protocols for integrating bone health into the comprehensive management of this population.
As shown in the results, patients with PSC awaiting liver transplantation experience a lower mortality rate due to liver disease compared to those suffering from other end-stage liver conditions. Previous research has also corroborated these findings47–50.
The strength of this study lies in its comprehensive assessment of bone mineral density at multiple skeletal sites in a relatively large and diverse cohort of patients with various chronic liver disease etiologies awaiting liver transplantation. Evaluating BMD at the lumbar spine, femoral neck, and total hip provided a more complete picture of skeletal health, while the inclusion of multiple disease etiologies strengthens the internal validity of our study and provides a comprehensive overview of bone health across the spectrum of chronic liver diseases encountered in a transplant setting. The large sample size also increased the statistical power to detect clinically meaningful associations between osteoporosis and survival outcomes, underscoring the importance of bone health assessment in pre-transplant evaluation.
The primary limitation of this study is its focus on isolating the effect of ESLD on bone health, which led to the exclusion of patients with other metabolic bone disorders. While this may limit generalizability, it was a necessary step to establish the independent prognostic value of osteoporosis specifically related to liver disease. The strong association found even in this refined cohort underscores the profound impact of hepatic osteodystrophy on patient survival.
Conclusion
This study demonstrates that osteoporosis is not merely a comorbidity but a clinically significant predictor of mortality in patients with chronic liver disease awaiting liver transplantation. The high prevalence of low BMD across diverse etiologies, particularly in patients with autoimmune hepatitis, emphasizes the systemic vulnerability of this population. Importantly, osteoporosis was independently associated with reduced waitlist survival, suggesting that bone health reflects broader physiological decline.
Acknowledgements
We want to express our sincere gratitude to the Abu-Ali Sina Hospital Organ Transplantation Center and its staff for their valuable contributions and support during this research. Their professionalism, dedication, willingness to share resources, and cooperation have been commendable. We would also like to express our gratitude for the financial support provided by the Vice Chancellor for Research and Technology at Shiraz University of Medical Sciences for this study, number 26373.
Author contributions
Mohammad Hossein Dabbaghmanesh contributed to the study’s conception, design, and supervision. Material preparation and data collection were done by Arzhang Naseri, Ehsan Shojaeefard, Amirreza Sabahizadeh, Ramina Mofarrah, Marzieh Bakhshayeshkaram, Pedram Talezadeh, Fateme Sadat Sadeghi, Saeedreza Shirzadi, Yasaman Khadem, Mohammad Mahdi Dabbaghmanesh and analysis was performed by Seyed Taghi Heydari. The first draft of the manuscript was written by Arzhang Naseri and edited by Farnaz Atighi and Alireza Keshtkar. All authors read and approved the final manuscript.
Funding
This study was financially supported by the Vice Chancellor for Research and Technology at Shiraz University of Medical Sciences (Grant No. 26373).
Data availability
Data are available from the authors upon reasonable request to the corresponding author.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Human Ethics Committee of Shiraz University of Medical Sciences, with the approval code of IR.SUMS.REC.1401.362, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The ethical consent forms were completed by all study participants after they were fully informed about the study’s goals, cooperation, benefits, and potential harms.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Zarrinpar, A. & Busuttil, R. W. Liver transplantation: past, present and future. Nat. Reviews Gastroenterol. Hepatol.10 (7), 434–440 (2013). [DOI] [PubMed] [Google Scholar]
- 2.Fox, A. N. & Brown, R. S. Is the patient a candidate for liver transplantation? Clin. Liver Dis.16 (2), 435–448 (2012). [DOI] [PubMed] [Google Scholar]
- 3.Mazzaferro, V. et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol.10 (1), 35–43 (2009). [DOI] [PubMed] [Google Scholar]
- 4.Yao, F. Y. et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology33 (6), 1394–1403 (2001). [DOI] [PubMed] [Google Scholar]
- 5.Moreno, R. & Berenguer, M. Post-liver transplantation medical complications. Ann. Hepatol.5 (2), 77–85 (2006). [PubMed] [Google Scholar]
- 6.Crosbie, O., Freaney, R., McKenna, M., Curry, M. & Hegarty, J. Predicting bone loss following orthotopic liver transplantation. Gut44 (3), 430–434 (1999). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Monegal, A. et al. Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics. Osteoporos. Int.12, 484–492 (2001). [DOI] [PubMed] [Google Scholar]
- 8.Leidig-Bruckner, G. et al. Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study. Lancet357 (9253), 342–347 (2001). [DOI] [PubMed] [Google Scholar]
- 9.Guarino, M. et al. Osteoporosis across chronic liver disease. Osteoporos. Int.27, 1967–1977 (2016). [DOI] [PubMed] [Google Scholar]
- 10.Rodríguez-Aguilar, E. F. et al. (eds) Bone disease and liver transplantation: a review. Transplantation Proceedings. (Elsevier, 2021). [DOI] [PubMed]
- 11.Ninkovic, M., Love, S., Tom, B., Alexander, G. & Compston, J. High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation. Calcif. Tissue Int.69 (6), 321 (2001). [DOI] [PubMed] [Google Scholar]
- 12.Sanchez, A. J. & Aranda-Michel, J. Liver disease and osteoporosis. Nutr. Clin. Pract.21 (3), 273–278 (2006). [DOI] [PubMed] [Google Scholar]
- 13.Yadav, A. & Carey, E. J. Osteoporosis in chronic liver disease. Nutr. Clin. Pract.28 (1), 52–64 (2013). [DOI] [PubMed] [Google Scholar]
- 14.Gatta, A., Verardo, A., Di Pascoli, M., Giannini, S. & Bolognesi, M. Hepatic osteodystrophy. Clin. Cases Mineral. Bone Metabolism. 11 (3), 185 (2014). [PMC free article] [PubMed] [Google Scholar]
- 15.Guañabens, N. & Parés, A. Osteoporosis in chronic liver disease. Liver Int.38 (5), 776–785 (2018). [DOI] [PubMed] [Google Scholar]
- 16.Handzlik-Orlik, G., Holecki, M., Wilczyński, K. & Duława, J. Osteoporosis in liver disease: pathogenesis and management. Therapeutic Adv. Endocrinol. Metabolism. 7 (3), 128–135 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Danford, C. J., Trivedi, H. D. & Bonder, A. Bone health in patients with liver diseases. J. Clin. Densitometry. 23 (2), 212–222 (2020). [DOI] [PubMed] [Google Scholar]
- 18.Jeong, H. M. & Kim, D. J. Bone diseases in patients with chronic liver disease. Int. J. Mol. Sci.20(17), 4270 (2019). [DOI] [PMC free article] [PubMed]
- 19.Danford, C. J., Trivedi, H. D. & Bonder, A. Bone health in patients with liver diseases. J. Clin. Densitom. 23 (2), 212–222 (2020). [DOI] [PubMed] [Google Scholar]
- 20.Sharma, P. et al. Bone mineral density predicts posttransplant survival among hepatocellular carcinoma liver transplant recipients. Liver Transpl.22 (8), 1092–1098 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Piano, S., Romano, A., Di Pascoli, M. & Angeli, P. Why and how to measure renal function in patients with liver disease. Liver Int.37 (S1), 116–122 (2017). [DOI] [PubMed] [Google Scholar]
- 22.Angeli, P. et al. EASL clinical practice guidelines for the management of patients with decompensated cirrhosis. J. Hepatol.69 (2), 406–460 (2018). [DOI] [PubMed] [Google Scholar]
- 23.Kamath, P. S. et al. A model to predict survival in patients with end-stage liver disease. Hepatology33 (2), 464–470 (2001). [DOI] [PubMed] [Google Scholar]
- 24.Wiesner, R. H. et al. MELD and PELD: application of survival models to liver allocation. Liver Transpl.7 (7), 567–580 (2001). [DOI] [PubMed] [Google Scholar]
- 25.Shuhart, C. R. et al. Executive summary of the 2019 ISCD position development conference on monitoring treatment, DXA cross-calibration and least significant change, spinal cord injury, peri-prosthetic and orthopedic bone health, transgender medicine, and pediatrics. Journal of Clinical Densitometry. 22(4):453–71. (2019). [DOI] [PubMed]
- 26.Krueger, D. et al. DXA reporting updates: 2023 official positions of the international society for clinical densitometry. J. Clin. Densitometry. 27 (1), 101437 (2024). [DOI] [PubMed] [Google Scholar]
- 27.Ferrari, S. et al. Osteoporosis in young adults: pathophysiology, diagnosis, and management. Osteoporos. Int.23, 2735–2748 (2012). [DOI] [PubMed] [Google Scholar]
- 28.Pepe, J. et al. Osteoporosis in premenopausal women: a clinical narrative review by the ECTS and the IOF. J. Clin. Endocrinol. Metabolism. 105 (8), 2487–2506 (2020). [DOI] [PubMed] [Google Scholar]
- 29.Heinze, G. & Dunkler, D. Five Myths about variable selection. Transpl. Int.30 (1), 6–10 (2017). [DOI] [PubMed] [Google Scholar]
- 30.Grant, S. W., Hickey, G. L. & Head, S. J. Statistical primer: multivariable regression considerations and pitfalls. Eur. J. Cardiothorac. Surg.55 (2), 179–185 (2019). [DOI] [PubMed] [Google Scholar]
- 31.Sokhi, R. P. et al. Bone mineral density among cirrhotic patients awaiting liver transplantation. Liver Transpl.10 (5), 648–653 (2004). [DOI] [PubMed] [Google Scholar]
- 32.Vargas, A. A. et al. (eds) Prevalence and characteristics of bone disease in cirrhotic patients under evaluation for liver transplantation. Transplantation proceedings, (Elsevier, 2012). [DOI] [PubMed]
- 33.Wibaux, C. et al. Assessing bone status in patients awaiting liver transplantation. Joint Bone Spine. 78 (4), 387–391 (2011). [DOI] [PubMed] [Google Scholar]
- 34.Loria, I. et al. (eds) Bone disorders in patients with chronic liver disease awaiting liver transplantation. Transplantation proceedings, (Elsevier, 2010). [DOI] [PubMed]
- 35.Compston, J. Glucocorticoid-induced osteoporosis: an update. Endocrine61 (1), 7–16 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Schmidt, T. et al. A system to determine risk of osteoporosis in patients with autoimmune hepatitis. Clin. Gastroenterol. Hepatol.18 (1), 226–233 (2020). e3. [DOI] [PubMed] [Google Scholar]
- 37.Chenbhanich, J., Thongprayoon, C., Atsawarungruangkit, A., Phupitakphol, T. & Cheungpasitporn, W. Osteoporosis and bone mineral density in patients with wilson’s disease: a systematic review and meta-analysis. Osteoporos. Int.29, 315–322 (2018). [DOI] [PubMed] [Google Scholar]
- 38.Loosen, S. H. et al. Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of osteoporosis and bone fractures. Z. Gastroenterol.60 (08), 1221–1227 (2022). [DOI] [PubMed] [Google Scholar]
- 39.Rodríguez-Alvear, C. et al. Osteoporosis assessment and outcomes in candidates for liver transplantation in a tertiary center: abstract number: 1135. Arthritis Rheumatol.73, 2354–2355 (2021).34105317 [Google Scholar]
- 40.Carranza, F. H., Miguel, G. A. & Librizzi, M. S. Post-Transplant Osteoporosis. Endotext. (2000).
- 41.Chen, T-L. et al. Risk and adverse outcomes of fractures in patients with liver cirrhosis: two nationwide retrospective cohort studies. BMJ Open.7 (10), e017342 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Shirinezhad, A. et al. Prevalent osteoporosis and fracture risk in patients with hepatic cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol.25 (1), 115 (2025). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Compston, J. E. Osteoporosis after liver transplantation. Liver Transpl.9 (4), 321–330 (2003). [DOI] [PubMed] [Google Scholar]
- 44.Saeki, C., Saito, M. & Tsubota, A. Association of chronic liver disease with bone diseases and muscle weakness. J. Bone Min. Metab.42 (4), 399–412 (2024). [DOI] [PubMed] [Google Scholar]
- 45.Zavatta, G. et al. High bone fracture risk in a large modern cohort of liver transplant recipients. Intern. Emerg. Med.20 (1), 139–150 (2025). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Lai, J. C. et al. Malnutrition, Frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American association for the study of liver diseases. Hepatology74 (3), 1611–1644 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Goldberg, D., French, B., Thomasson, A., Reddy, K. R. & Halpern, S. D. Waitlist survival of patients with primary sclerosing cholangitis in the model for end-stage liver disease era. Liver Transpl.17 (11), 1355–1363 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Goyes, D. et al. Waitlist mortality in patients with autoimmune liver diseases. Ann. Hepatol.27 (6), 100742 (2022). [DOI] [PubMed] [Google Scholar]
- 49.Fink, M. A. et al. Risk factors for liver transplantation waiting list mortality. J. Gastroenterol. Hepatol.22 (1), 119–124 (2007). [DOI] [PubMed] [Google Scholar]
- 50.Staufer, K. et al. Waitlist mortality and post-transplant survival in patients with cholestatic liver disease–Impact of changes in allocation policy. HPB20 (10), 916–924 (2018). [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available from the authors upon reasonable request to the corresponding author.