Introduction
Osteoporosis is a generalized skeletal disease
characterized by increased bone resorption and decreased bone
formation, and is associated with an increased risk of bone
fractures. The prevalence of osteoporosis has been increasing in
Japan (1,2). Osteoporosis is classified as primary,
secondary and idiopathic, with the term hepatic osteodystrophy
first being defined in 1960 and including secondary osteoporosis
(3). The prevalence of bone disease in
patients with liver disease is higher than in the general
population (4,5), as the majority of patients with chronic
liver disease exhibit multiple risk factors for osteodystrophy,
such as protein-calorie malnutrition and vitamin D deficiency.
Osteoporosis is common in patients with cirrhosis, biliary disease
(6,7) and
alcoholism (8). However, hepatic
osteodystrophy has gained little attention, as, compared with
hepatocellular carcinoma and esophageal varices, it does not
significantly affect life expectancy.
Advances in medical technology have prolonged life
expectancy in patients with liver diseases. Osteoporosis decreases
the quality of life, as it causes an increased risk of bone
fractures. Therefore, hepatic osteodystrophy is considered to be a
subject of interest.
In Japan, there have been few studies on
osteoporosis in patients with end-stage liver disease (ESLD).
Therefore, the clinical features of osteoporosis were examined in
patients with ESLD and the associated risk factors were
identified.
Materials and methods
Patient characteristics
The present study included 79 patients with ESLD
admitted to Nagasaki University Hospital (Nagasaki, Japan) between
June 2008 and October 2012. ESLD was defined as a patient who
registered as a recipient of liver transplantation at Nagasaki
University. Furthermore, patients were eligible to take part if
they were aged ≥18 years and had ESLD. Patients who were
administered medication for osteoporosis were excluded. The current
study included 2 patients with Child-Pugh class A; however, these
patients exhibited portal hypertension and experienced difficulties
during therapy for bleeding varices. The etiology of chronic liver
disease was based on clinical, analytical and radiological
criteria. The current cohort included 40 males (50.6%) with a mean
age of 57.0 years (range 24–75 years). The median Child-Pugh score
was 10.0 and the model for ESLD (MELD) score was 14.00. All
patients provided informed consent, and the study protocol
conformed to the guidelines of the Declaration of Helsinki and was
approved by the Nagasaki University Ethics Committee (approval no.
16042537). Patient characteristics are summarized in Table I.
 | Table I.Baseline characteristics of the
patients (n=79). |
Table I.
Baseline characteristics of the
patients (n=79).
| Variables | Value |
|---|
| Age, years | 57.0 (24–75) |
| Gender |
|
| Male n
(%) | 40 (50.6) |
| Female
n(%) | 39 (49.4) |
| Etiology, n (%) |
|
|
Viral | 51 (64) |
| HCV | 38 (47) |
| HBV | 13 (17) |
|
Alcohol | 10 (13) |
| PBC | 7 (9) |
| AIH | 4 (5) |
| PSC | 3 (3) |
| NASH | 2 (3) |
|
Other | 2 (3) |
| Body mass index | 24.7 |
| MELD score | 14 |
| Child-Pugh score | 10 |
| Diabetes, n (%) | 33 (41) |
| HCC, n (%) | 35 (44) |
| Compression fracture,
n (%) | 17 (21.5) |
| Osteoporosis, n
(%) | 23/79 (29.1) |
| Male, n
(%) | 7/40 (17.5) |
| Female, n
(%) | 16/39 (41.0) |
| AST (IU/l) | 37.0 (12–154) |
| ALT (IU/l) | 41.0 (19–244) |
| ALP (IU/l) | 415.0 (171–1180) |
| BTR (µmol/l) | 3.00 (1.58–7.24) |
| ChE (IU/l) | 102.7 (36–279) |
| Total bile acid
(µmol/l) | 145.1
(7.4–639.5) |
| Albumin (g/dl) | 2.80 (1.9–4.2) |
| T-Cho (mg/dl) | 123.0 (50–331) |
| Bone-ALP (U/l) | 24.9 (7.9–44.2) |
| Osteocalcin
(ng/ml) | 5.60 (1–32) |
| Urine-NTx/CR (nmol
BCE/mmol CR) | 37.3
(11.3–142.4) |
| Hemoglobin
(g/dl) | 10.6 (6.2–17.3) |
| Platelet
(104/µl) | 6.20 (2.2–27.3) |
| BMD (T-score)
spine | −1.90 (−5.5–4.3) |
The following clinical items were collected at
enrolment for each patient: Age, gender, body mass index (BMI),
Child-Pugh score, MELD score, and treatments that could affect bone
mineral density (BMD; corticosteroids, hormone replacement therapy,
calcium and vitamin supplementation, and antiosteoporotic agents,
taken either currently or in the last 24 months).
In addition, the results of recent blood tests
(within 1 month) were collected: Serum bilirubin, alanine
aminotransferase (ALT), aspartate transaminase (AST), alkaline
phosphatase, γ-glutamyl transferase, platelet count, prothrombin
time, albumin, total cholesterol and total bile acid.
Assessment of bone mineral
density
BMD was assessed by dual-energy X-ray absorptiometry
(DEXA) using a Norland XR-46 DEXA (Swissray Global Healthcare
Holding Ltd., Taipei, Taiwan) scan of the lumbar spine. Norland
XR-46™ software was used to compute the BMD in mg/cm2
(of calcium hydroxyapatite equivalent), aggregate the results, and
compute the mean BMD and the T score. The T score was defined as
the number of standard deviations from the mean BMD values of
healthy young adults. Hepatic osteodystrophy was defined as the
presence of osteoporosis or osteopenia; osteopenia was defined as a
T score between −1 and −2.5, and osteoporosis was defined as a T
score <-2.5 below the reference value, or the existence of a
compression fracture with osteopenia (T score: World Health
Organization criteria) (9).
Statistical analysis
All statistical analysis was performed with
Stat-flex version 6 (Artech Co., Ltd., Osaka, Japan). The
Mann-Whitney U test was used for comparisons between groups. The
presence of osteoporosis in ESLD was analyzed with a
χ2-test. Receiver operating characteristic (ROC) curves
were used to determine an appropriate cut-off for the continuous
variable and P<0.05 was considered to indicate a statistically
significant difference.
Results
Correlation between clinical features
and bone mineral density
The T-score was significantly correlated with BMI
(r=0.430; P=0.001) and inversely correlated with total bile acid
(r=−0.228; P=0.049; Table II). A
significant correlation between the T-score and biochemical bone
metabolism factors was only identified for the urine N-telopeptide
type I collagen (NTx)/creatinine (CR) ratio (r=−0.280; P=0.024;
Table III).
| Table II.Correlation between clinical data and
bone mineral density. |
Table II.
Correlation between clinical data and
bone mineral density.
| Variables | Correlation
coefficient | P-value |
|---|
| Age | 0.164 | 0.149 |
| Body mass index | 0.430 | 0.001 |
| MELD score | −0.019 | 0.880 |
| Child-Pugh score | −0.153 | 0.205 |
| AST | 0.051 | 0.656 |
| ALT | −0.007 | 0.954 |
| ALP | −0.082 | 0.474 |
| BTR | −0.117 | 0.327 |
| ChE | 0.160 | 0.159 |
| Total bile acid | −0.228 | 0.049 |
| Albumin | 0.128 | 0.263 |
| T-Cho | 0.048 | 0.677 |
| Hemoglobin | 0.109 | 0.337 |
| Platelet | −0.076 | 0.503 |
| Prothrombin time
INR | −0.016 | 0.893 |
| Table III.Correlation between biochemical bone
metabolism data and bone mineral density. |
Table III.
Correlation between biochemical bone
metabolism data and bone mineral density.
| Variables | Correlation
coefficient | P-value |
|---|
| Urine NTx/CR | −0.280 | 0.024 |
| BAP | 0.024 | 0.841 |
| Osteocalcin | 0.052 | 0.673 |
| Corrected
calcium | −0.109 | 0.340 |
| Intact PTH | −0.127 | 0.289 |
| 1,25(OH)2 vitamin
D | 0.155 | 0.201 |
Clinical features in patients with and
without osteoporosis
Osteoporosis was observed in 23 of 79 (29%)
patients. Patients with osteoporosis were significantly older
(osteoporosis vs. no osteoporosis: 63.0 (24–75) vs. 56.0 (34–70)
years; P<0.05), had higher total bile acid (osteoporosis vs. no
osteoporosis: 306.0 (28.4–639.5) vs. 129.1 (7.2–631) µmol/l;
P<0.05) (Table IV) and higher
corrected calcium [osteoporosis vs. no osteoporosis: 9.85
(8.7–10.7) vs. 9.70 (8.8–10.6) mg/dl; P<0.05] (Table V).
| Table IV.Clinical, biological and biochemical
data in patients with and without osteoporosis. |
Table IV.
Clinical, biological and biochemical
data in patients with and without osteoporosis.
| Variables | Osteoporosis
(23/79) | No osteoporosis
(56/79) | P-value |
|---|
| Age (years) | 63.0 (24–75) | 56.0 (34–70) | <0.05 |
| Gender
(male/female) | 7/16 | 33/23 | <0.05 |
| BMI
(kg/m2) | 23.8
(18.4–30.2) | 25.3
(18.6–37.3) | N.S |
| MELD score | 14.5 (9–29) | 14.0 (6–34) | N.S |
| Child-Pugh
score | 10.0 (6–13) | 9.0 (6–15) | N.S |
| Diabetes
(%)a | 34.8 | 30.4 | N.S |
| HCC
(%)a | 47.8 | 41.1 | N.S |
| AST (IU/l) | 38.0 (14–128) | 34.0 (12–154) | N.S |
| ALT (IU/l) | 35.0 (1–56) | 44.0 (9–244) | N.S |
| ALP (IU/l) | 406.0 (178–46) | 415.0
(171–1185) | N.S |
| BTR (µmol/l) | 2.81
(1.54–8.17) | 3.07
(0.76–36.90) | N.S |
| ChE (IU/l) | 94.0 (36–179) | 91.5 (33–279) | N.S |
| Total bile acid
(µmol/l) | 306.0
(28.4–639.5) | 129.1
(7.2–631) | <0.05 |
| Albumin (g/dl) | 2.7 (2.0–3.7) | 2.9 (1.9–4.2) | N.S |
| T-Cho (mg/dl) | 105.0 (50–171) | 123.0 (51–331) | N.S |
| Hemoglobin
(g/dl) | 10.6
(7.9–14.1) | 10.7
(6.2–17.3) | N.S |
| Platelet
(104/µl) | 6.4 (2.1–26.3) | 6.0 (0.2–27.3) | N.S |
| Prothrombin time
INR | 1.41
(1.24–1.81) | 1.43
(0.99–3.28) | N.S |
| Compression
fracture (%) | 60.9 | 5.4 | <0.05 |
| Table V.Biochemical bone metabolism data in
patients with and without osteoporosis. |
Table V.
Biochemical bone metabolism data in
patients with and without osteoporosis.
| Variables | Osteoporosis
(23/79) | No osteoporosis
(56/79) | P-value |
|---|
| Urine NTx CR (nmol
BCE/mmol CR) | 47.2
(15.1–152.4) | 35.6
(11.3–98.3) | N.S |
| BAP (µg/l) | 25.3
(7.9–42.7) | 24.5
(11.8–91.0) | N.S |
| Osteocalcin
(ng/ml) | 5.6 (1–14) | 5.6 (1–32) | N.S |
| Corrected calcium
(mg/dl) | 9.85
(8.7–10.7) | 9.70
(8.8–10.6) | <0.05 |
| Intact PTH
(pg/dl) | 29.0
(14.0–93.0) | 26.0
(7.0–90.0) | N.S |
| 1,25(OH)2 vitamin D
(pg/ml) | 37.4
(16.0–67.0) | 36.9
(10.4–89.5) | N.S |
An increased number of females had osteoporosis
(osteoporosis vs. no osteoporosis, 69 vs. 41%; P<0.05) and the
prevalence of bone fractures was significantly higher in patients
with osteoporosis. Prevalence of osteoporosis tended to be higher
in cholestatic disease than in non-cholestatic disease, although
the difference was not significant [4/10 (40%) vs. 19/69 (27.5%);
P=0.07]. Among the biochemical bone metabolism markers, only
corrected calcium was significantly higher in patients with
osteoporosis. In multivariate analysis, age (β=−0.015±0.06;
P=0.009) and total bile acid (β=−0.001±0.0001; P=0.041) were
independent risk factors for osteoporosis (Table VI).
| Table VI.Independent risk factors for
osteoporosis in patients with end stage liver disease. |
Table VI.
Independent risk factors for
osteoporosis in patients with end stage liver disease.
| Variables | P-value | β |
|---|
| Gender | 0.362 | 0.096±0.105 |
| Age | 0.009 | −0.015±0.006 |
| Total bile
acid | 0.041 | −0.001±0.0001 |
| Corrected
calcium | 0.116 | −0.199±0.125 |
Among patients with hepatitis C virus, those with
osteoporosis were also significantly older [osteoporosis vs. no
osteoporosis: 60.7 (52–72) vs. 55.5 years (43–70); P<0.05]
(Table VII). They were more likely
to be female (male vs. female: 69 vs. 32%; P<0.05) and had
higher total bile acid levels [osteoporosis vs. no osteoporosis:
306.0 (28.4–639.5) vs. 129.1 (7.2–631) µmol/l; P<0.05]. Among
patients with cholestatic disease, those with osteoporosis had
higher total bile acid levels [osteoporosis vs. no osteoporosis:
305.7 (147.5–387.1) vs. 123.2 (67.3–212.2) µmol/l; P<0.05]
(Table VIII).
| Table VII.Clinical data in HCV patients with
and without osteoporosis (n=38). |
Table VII.
Clinical data in HCV patients with
and without osteoporosis (n=38).
| Variables | Osteoporosis
(n=13) | No osteoporosis
(n=25) | P-value |
|---|
| Age | 60.7 (52–72) | 55.5 (43–70) | <0.05 |
| Gender |
|
|
|
|
M/fa | 4/9 | 17/8 | <0.05 |
| Total bile
acid | 321.1
(41.2–639.5) | 200.8
(17.1–631) | <0.05 |
| Table VIII.Clinical data in cholestatic disease
patients with and without osteoporosis (n=10). |
Table VIII.
Clinical data in cholestatic disease
patients with and without osteoporosis (n=10).
| Variables | Osteoporosis
(n=4) | No osteoporosis
(n=6) | P-value |
|---|
| Age | 52.5 (24–65) | 57.6 (43–70) | N.S |
| Gender |
|
|
|
|
M/fa | 0/4 | 2/4 | N.S |
| Total bile
acid | 305.7
(147.5–387.1) | 123.2
(67.3–212.2) | <0.05 |
Risk score for osteoporosis
The risk score for osteoporosis was defined based on
multivariate analysis as follows: Risk score=1.78 - 0.001 × total
bile acid - (0.16 × age). The area under the ROC curve was
0.778.
Discussion
The present study revealed that BMD was
significantly correlated with BMI and total bile acid. Previous
studies reported that a low BMI and malnutrition were risk factors
for osteoporosis and bone fractures (10,11). Low BMI
was associated with malnutrition; therefore, in patients with ESLD,
malnutrition was considered to be a factor as important as
osteodystrophy.
The elevation of total bile acid is associated with
the impairment of enterohepatic circulation (12). In the current study, total bile acid
showed an inverse correlation with BMD in patients with ESLD. A
significant difference between patients with and without
osteoporosis was also found for total bile acid. In addition,
significant differences were identified in total bile acid levels
in patients with chronic hepatitis C and cholestatic disease. The
mechanism is as follows: The impairment of bile acid secretion in
the intestine decreases the formation of lipid soluble vitamins,
including vitamin D (13,14). The activated vitamin D regulates
calcium absorption and BMD. Furthermore, previous reports have
shown that bile duct ligated rats had severe cholestasis, but
developed low turnover osteoporosis (15).
Among biochemical bone metabolism markers, only
urine NTx/CR was significantly negatively correlated with BMD.
Among bone resorption markers, urine NTx/CR is the most frequently
used in clinical practice (16). This
biochemical bone metabolism marker changes prior to alterations in
BMD. Therefore, urine NTx/CR may be an effective marker of BMD in
patients with ESLD. However, osteogenic markers, such as
osteocalcin and bone specific alkaline phosphatase were not
correlated with BMD. This indicated that bone resorption was
greater in patients with ESLD.
In the present study, the prevalence of osteoporosis
was 29% (17.5% in males and 41.0% in females). According to the
Japanese Society for Bone and Mineral Research, the prevalence of
osteoporosis in the Japanese general population is 4% in males and
24% in females (17). Therefore, ESLD
is a major risk factor for osteoporosis. The observed prevalence in
patients with ESLD was consistent with previous reports (18–20).
Previous studies have reported that cholestatic
liver disease, including primary biliary cirrhosis and primary
sclerosing cholangitis are risk factors for osteoporosis (21–23).
However, in the current study, the prevalence of osteoporosis
tended to be higher in cholestatic disease than in non-cholestatic
disease, although there was no significant difference identified.
The reason for this is that the study did not include non-cirrhotic
disease. The majority of patients with ESLD have a certain level of
cholestasis. The current study demonstrated that cholestasis is a
major risk factor for osteoporosis.
Significant differences between patients with and
without osteoporosis were observed for age, female gender and total
bile acid. Upon multivariate analysis, age and total bile acid were
identified as risk factors for osteoporosis and predictive scores
for osteoporosis were devised for patients with ESLD. If the score
is ≤0.174, sensitivity is 0.815 and specificity is 0.62, patients
require DEXA and treatment.
There were certain limitations of the present study.
This was a retrospective study from a single hospital and had a
small sample size. In future, a study of patients with ESLD from
multiple centers is required to validate the current results.
In conclusion, age and total bile acid were
identified as significant predictors of osteoporosis in patients
with ESLD. In addition, the risk score calculated by multivariate
analysis may be a useful marker for the prediction of osteoporosis
in patients with ESLD.
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