primary sclerosing cholangitis ( psc ) is a chronic and progressive disease of the liver .
patients with psc frequently have asymptomatic and anicteric cholestasis and many of them develop progressive biliary strictures , which lead to recurrent cholangitis , biliary cirrhosis and end - stage liver disease .
these complications along with symptoms of the disease , such as chronic fatigue , pruritus , impaired memory and concentration , excessive daytime sleepiness and symptoms of frequently coexisting chronic inflammatory bowel disease ( ibd ) or liver cirrhosis may substantially influence patients health - related quality of life ( hrqol ) ( 1 , 2 ) .
it is widely accepted that evaluation of hrqol as a multidimensional construct encompassing physical and cognitive capabilities , functional behavior , emotional status and psychosocial adjustment , plays an important role in the holistic care of patients with chronic liver diseases ( 3 , 4 ) .
osteoporosis is a frequent comorbidity in chronic liver diseases ( 1 ) , leading to fragility fractures associated with significant morbidity , mortality and further impairment of hrqol ( 5 ) .
in contrast to other chronic liver conditions , clinical consequences of osteoporosis in psc have been less intensively studied .
particularly , to date , there have been no previous reports evaluating the fracture rate and the impact of fractures on hrqol outcomes in patients with psc .
the aim of this study was to assess bone mineral density ( bmd ) measured by dual - energy x - ray absorptiometry ( dxa ) , physical activity and incidence of fragility fractures in patients with psc .
this study was performed on 33 patients with psc ( 11 females , 22 males ) aged 35.3  13.38 years ( ranged 19.5 to 69.4 years ) .
psc was diagnosed using the european association for the study of the liver ( easl ) criteria as : 1 ) elevated serum markers of cholestasis ; and 2 ) typical bile duct changes in magnetic resonance imaging or endoscopic cholangiography ( 6 ) .
we included only those patients who had no other acute or chronic medical conditions that required pharmacological treatment or might influence hrqol outcomes .
we excluded patients with a history of rapid weight changes within the last 12 months . among the included patients , six had an established liver cirrhosis and 20 had ibd , including 12 cases with ulcerative colitis , two with crohn s disease and six with non - classified colitis .
the bowel disease was in remission in all patients .   in all subjects , we measured weight and height . based on available medical reports , we collected the following data on the past fragility fractures , location of the fracture and its severity , time since diagnosis of psc , x - ray imaging and type of trauma .
fragility fractures were defined as fractures of the distal forearm , neck of the femur , rib and vertebral body occurred as a result of a minimal trauma , such as a fall from a standing height or less or without identifiable trauma .
blood samples were obtained to assess aminotransferases , alkaline phosphatase and bilirubin after an overnight fast from each study participant .
the study protocol was approved by the ethics committee of the pomeranian medical university and conformed to the ethical guidelines of the 1975 declaration of helsinki ( 6 revision , 2008 ) . bone mineral density ( bmd ) was measured in the lumbar spine ( l1 - l4 ) and the hip by dual - energy x - ray absorptiometry ( dxa ) ( ge lunar prodigy ; madison , wi ; usa ; software encore version 14.1 ) using automatic scan modes . osteopenia and osteoporosis
were diagnosed according to the world health organization ( who ) criteria ( 7 ) .
bmd values were expressed in g / cm as well as z - scores ( standard deviation from the mean bmd for normal , age - matched , gender - specific subjects ) and t - scores ( standard deviation from the mean bmd for normal young individuals ) .
bmd values were compared with expected normal bmd and adjusted for gender and ethnicity using standard values for normal population provided by the manufacturer s reference database . additionally , we measured total body fat ( bf ) and lean mass from the total body scan using an automatic scan mode .
the coefficients of variation of lumbar spine , hip and total body measurements were 0.9% , 1.5% and below 1.0% , respectively .
three questionnaires were used for data collection : 1 ) the medical outcome study short form-36 ( sf-36 ) ; 2 ) pbc-40 ; and 3 ) pbc-27 .
the medical outcomes study short form 36 ( sf-36 ) is a widely used and validated generic questionnaire to measure hrqol in various populations with a wide variety of medical conditions ( 8 , 9 ) .
the disease - specific instruments , pbc-40 and pbc-27 assess the symptoms of chronic cholestasis such as fatigue , excessive daytime sleepiness , pruritus and impaired memory and concentration ( 3 , 4 ) .
sf-36 includes 36 items divided into eight domains of physical health ( physical functioning , role limitation - physical , bodily pain and general health ) and mental health ( vitality , social functioning , role limitation - emotional and mental health ) .
scale scores ranged from 0 ( denoting the most impaired hrqol ) and 100 ( ideal well - being ) and two summary scores ; the physical component score ( pcs ) and mental component score ( mcs ) were also calculated .  
pbc-40 is nowadays commonly used in the assessment of hrqol in patients with primary biliary cirrhosis ( 3 ) .
six domains of pbc-40 relate to fatigue , emotional , social and cognitive functions , general symptoms and itching .
answers are marked on a five - point likert scale ( from 1 = never to 5 = always ) , with higher scores denoting greater impact of symptoms and poorer hrqol .
possible range of each domain was symptom domain 7 - 35 , itching 3 - 15 , fatigue 11 - 55 , cognitive 6 - 30 and social and emotional functions 13 - 65 points ( 10 ) .
pbc-40 was also used in hrqol evaluation in patients with psc ( 11 ) .  
pbc-27 is an alternative structure of the hrqol questionnaire for pbc , which appears to be simpler and equivalently sufficient in detecting the impact of pbc on patients well - being .
twenty seven items are grouped into the following domains : other symptoms ( possible range : 3 - 15 points ) , dryness ( 2 - 10 points ) , itching ( 3 - 15 points ) , fatigue ( 8 - 40 points ) , cognitive ( 5 - 25 points ) , emotional ( 3 - 15 points ) and social ( 3 - 15 points ) functions are evaluated on the same five - point scale as pbc-40 ( 4 ) .  
the international physical activity questionnaire ( ipaq ) was used as a self - report measure of habitual physical activity , with a 7-day recall of physical activity within a month .
ipaq consists of 27 questions regarding four life domains : physical activity associated with the occupation performed , work at home and around the house , moving to various places and mobility during free time devoted to recreation , playing games , sports , tourism or other muscular work and additional time spending in the sitting position .
total physical activity as measured by ipaq is categorized as low ( below 600 met minute / week ) , moderate ( from 600 to 3000 met minute / week ) and vigorous ( above 3000 met minute / week ) .
data are presented as means  standard deviation ( sd ) or numbers ( proportion ) of patients with a condition .
shapiro - wilk test was used to test for normality , while f - test ( snedecor ) and brown - forsythe test were used to assess the homogeneity of variances . in the case of a normal distribution and equal variances , means were compared by student s t - test ; otherwise , non - parametric methods were used .
the chi - squared test for independence with a yates correction was used to analyze qualitative variables . the relationship between pairs of quantitative variables
this study was performed on 33 patients with psc ( 11 females , 22 males ) aged 35.3  13.38 years ( ranged 19.5 to 69.4 years ) .
psc was diagnosed using the european association for the study of the liver ( easl ) criteria as : 1 ) elevated serum markers of cholestasis ; and 2 ) typical bile duct changes in magnetic resonance imaging or endoscopic cholangiography ( 6 ) .
we included only those patients who had no other acute or chronic medical conditions that required pharmacological treatment or might influence hrqol outcomes .
we excluded patients with a history of rapid weight changes within the last 12 months . among the included patients , six had an established liver cirrhosis and 20 had ibd , including 12 cases with ulcerative colitis , two with crohn s disease and six with non - classified colitis .
the bowel disease was in remission in all patients .   in all subjects , we measured weight and height . based on available medical reports , we collected the following data on the past fragility fractures , location of the fracture and its severity , time since diagnosis of psc , x - ray imaging and type of trauma .
fragility fractures were defined as fractures of the distal forearm , neck of the femur , rib and vertebral body occurred as a result of a minimal trauma , such as a fall from a standing height or less or without identifiable trauma .
blood samples were obtained to assess aminotransferases , alkaline phosphatase and bilirubin after an overnight fast from each study participant .
the study protocol was approved by the ethics committee of the pomeranian medical university and conformed to the ethical guidelines of the 1975 declaration of helsinki ( 6 revision , 2008 ) .
bone mineral density ( bmd ) was measured in the lumbar spine ( l1 - l4 ) and the hip by dual - energy x - ray absorptiometry ( dxa ) ( ge lunar prodigy ; madison , wi ; usa ; software encore version 14.1 ) using automatic scan modes . osteopenia and osteoporosis
were diagnosed according to the world health organization ( who ) criteria ( 7 ) .
bmd values were expressed in g / cm as well as z - scores ( standard deviation from the mean bmd for normal , age - matched , gender - specific subjects ) and t - scores ( standard deviation from the mean bmd for normal young individuals ) .
bmd values were compared with expected normal bmd and adjusted for gender and ethnicity using standard values for normal population provided by the manufacturer s reference database . additionally , we measured total body fat ( bf ) and lean mass from the total body scan using an automatic scan mode .
the coefficients of variation of lumbar spine , hip and total body measurements were 0.9% , 1.5% and below 1.0% , respectively .
three questionnaires were used for data collection : 1 ) the medical outcome study short form-36 ( sf-36 ) ; 2 ) pbc-40 ; and 3 ) pbc-27 .
the medical outcomes study short form 36 ( sf-36 ) is a widely used and validated generic questionnaire to measure hrqol in various populations with a wide variety of medical conditions ( 8 , 9 ) .
the disease - specific instruments , pbc-40 and pbc-27 assess the symptoms of chronic cholestasis such as fatigue , excessive daytime sleepiness , pruritus and impaired memory and concentration ( 3 , 4 ) .
sf-36 includes 36 items divided into eight domains of physical health ( physical functioning , role limitation - physical , bodily pain and general health ) and mental health ( vitality , social functioning , role limitation - emotional and mental health ) .
scale scores ranged from 0 ( denoting the most impaired hrqol ) and 100 ( ideal well - being ) and two summary scores ; the physical component score ( pcs ) and mental component score ( mcs ) were also calculated .  
pbc-40 is nowadays commonly used in the assessment of hrqol in patients with primary biliary cirrhosis ( 3 ) .
six domains of pbc-40 relate to fatigue , emotional , social and cognitive functions , general symptoms and itching .
answers are marked on a five - point likert scale ( from 1 = never to 5 = always ) , with higher scores denoting greater impact of symptoms and poorer hrqol .
possible range of each domain was symptom domain 7 - 35 , itching 3 - 15 , fatigue 11 - 55 , cognitive 6 - 30 and social and emotional functions 13 - 65 points ( 10 ) .
pbc-40 was also used in hrqol evaluation in patients with psc ( 11 ) .  
pbc-27 is an alternative structure of the hrqol questionnaire for pbc , which appears to be simpler and equivalently sufficient in detecting the impact of pbc on patients well - being .
twenty seven items are grouped into the following domains : other symptoms ( possible range : 3 - 15 points ) , dryness ( 2 - 10 points ) , itching ( 3 - 15 points ) , fatigue ( 8 - 40 points ) , cognitive ( 5 - 25 points ) , emotional ( 3 - 15 points ) and social ( 3 - 15 points ) functions are evaluated on the same five - point scale as pbc-40 ( 4 ) .
the international physical activity questionnaire ( ipaq ) was used as a self - report measure of habitual physical activity , with a 7-day recall of physical activity within a month .
ipaq consists of 27 questions regarding four life domains : physical activity associated with the occupation performed , work at home and around the house , moving to various places and mobility during free time devoted to recreation , playing games , sports , tourism or other muscular work and additional time spending in the sitting position .
total physical activity as measured by ipaq is categorized as low ( below 600 met minute / week ) , moderate ( from 600 to 3000 met minute / week ) and vigorous ( above 3000 met minute / week ) .
data are presented as means  standard deviation ( sd ) or numbers ( proportion ) of patients with a condition .
shapiro - wilk test was used to test for normality , while f - test ( snedecor ) and brown - forsythe test were used to assess the homogeneity of variances . in the case of a normal distribution and equal variances , means
were compared by student s t - test ; otherwise , non - parametric methods were used . the chi - squared test for independence with a yates correction
baseline characteristics of patients and comparisons between the subjects with and without fractures are summarized in table 1 . in psc patients , mean bmd of hip was 0.97 + 0.183 g / cm and of spine was 1.11 + 0.161 g / cm . in comparison with males , females had lower hip bmd ( 1.02  0.015 vs. 0.88  0.21 g / cm ; p = 0.043 ) and comparable spine bmd ( 1.12  0.18 vs. 1.07  0.08 g / cm ) . in all subjects ,
mean bmd values were moderately but significantly lower in psc than expected in a matched young healthy population of the same gender and ethnicity using the reference values provided by the manufacturer s database ( p = 0.011 in the lumbar spine and p = 0.044 in the hip ) .
based on the who densitometric criteria ( 7 ) , one patient ( 3% ) had osteoporosis and 9 ( 27.3% ) osteopenia either in the lumbar spine or hip .
the incidence of a lowered bmd at any site ( z - score below  1.0 sd ) was not associated with presence of ibd or liver cirrhosis ( p > 0.05 ) .
as many as 75% of patients declared low to moderate physical activity ( below 3000 met / minute / week ) . in the sf-36 assessment
, patients marked the lowest scoring in the general health domain and the highest in the role emotional domain .
in both pbc-40 and pbc-27 , patients frequently marked fatigue as well as social and emotional domains as affecting their hrqol .  
five of the patients who had experienced fractures also had ibd , while none of them had liver cirrhosis .
three subjects with fractures had the lumbar spine and hip bmd t - scores between 1.0 and 2.5 sd ; the remaining had normal bmd.we did not find significant differences in gender distribution , age , duration of psc , bmd measurement , the incidence of ibd and liver cirrhosis and body composition between individuals with and without fractures .
on the other hand , in patients who had experienced fragility fractures , mean scores in role functioning , general health , vitality and pcs domains in sf-36 were lower than subjects without fractures .
a similar trend was also observed in respect of the mcs domain . in multiple regression analysis , prior fractures adjusted for gender , age and duration of psc
were significantly associated with lower pcs (  = -0.506 ; 95% ci : from -0.856 to -0.155 ; p = 0.006 ) and mcs scores (  = -0.416 ; 95% ci : from -0.791 to -0.039 ; p = 0.031 ) .  
mcs and pcs ( except for itching ) were inversely correlated with all domains tested by pbc-40 and pbc-27 ( table 2 ) . however , in multiple regression analysis , symptoms and fatigue scores and prior fractures were inversely associated with mcs (  = -7.19 ; 95% ci : from -22.2 to -10.1 ; p = 0.007 ) , but not pcs scores ( p = 0.124 ) .
interestingly , prior fractures were not associated with a lower bmd below 1.0 sd in either sites ( r = 0.104 ; p = 0.144 ) . in both pbc-40 and pbc-27 ,
patients with fractures reported higher scores in symptoms and fatigue domains than subjects without fractures . moreover in pbc-27 , patients with fractures reported higher scores in dryness and emotional domains .
as shown in table 3 , bmd values did not correlate with age , bmi , duration of psc , fat mass and total physical activity .
there was a positive correlation between lean mass ( but not fat mass ) and hip bmd .
lean mass was also positively correlated with total physical activity ( r = 0.424 ; p = 0.03 ) .  
in the current study on young and middle - aged subjects with psc lasting for approximately three years , we found a high rate of fragility fractures and moderately lower bmd values in the lumbar spine and hip .
in several studies performed on patients with psc , similar ( 13 ) or even higher rates of low bmd , reaching 50% of patients ( 14 , 15 ) were observed .
inconsistent to our results , these studies suggested that low bone mass in psc might be associated with advanced age , low bmi , severity of psc or long duration of ibd ( 14 ) .
however , patients participating in those studies were older and had a longer duration of psc than our population .
this is consistent with other reports indicating more advanced metabolic bone disease in psc associated with end - stage liver disease evaluated for transplantation ( 16 ) or with advanced liver cirrhosis ( 17 ) .
additionally , advanced age and low bmi are well - known risk factors for reduced bmd in general population .
our results suggested that even young patients with psc with a relatively short duration of the disease are at risk of osteoporosis .
previous studies demonstrated that ibd per se is associated with an increased prevalence of bone demineralization and low energy fractures ( 2 ) .
however , ibd associated with psc usually follows a more quiescent course than patients without psc ( 18 - 20 ) . in patients with psc , angulo et al .
( 14 ) found a 3.6-fold increased risk for osteoporosis in cases with duration of ibd more than 19 years .
moreover , in their study the rate of bone loss per year was significantly associated with duration of ibd .
hence , we speculate that in patients with a relatively short duration of disease , ibd might be a potential risk factor , but not yet a robust predictor of osteoporosis , although the relative impact of ibd - associated factors and ibd - specific inflammation on bone health is still uncertain ( 2 ) . we found a positive correlation between hip bmd and lean mass .
recent meta - analysis ( 21 ) and observational studies in men ( 22 ) and women ( 23 ) demonstrated that lean tissue contributes more to bone mass in the femur than fat tissue during life in healthy population , and now , as suggested by this study possibly also in psc .
this finding underlines the concept that in psc , in which bmd is frequently lower , physical activity is an important component in the maintenance of bone loss and prevention of osteoporosis .
because lean tissue is composed mainly of skeletal muscles , it influences bone directly via mechanical stimuli and myokines ( 24 ) .
therefore , a low lean mass seems to be an important risk factor of vertebral and hip fractures , ranking in importance alongside age ( 21 ) . in line with this concept
, we found positive associations between lean mass , hip bmd and the intensity of physical activity . in the current study ,
there have been no previous reports evaluating fracture rate in psc . in postmenopausal women with primary biliary cirrhosis ,
regardless of the small sample size , our results suggested that this prevalence may be even higher in psc .
we found that patients with fractures had significantly lower sf-36 role functioning , general health , vitality and pcs scores than those without fractures ; a similar trend was also observed regarding mcs domain .
moreover , in multiple regression analysis , prior fractures adjusted for gender , age and duration of psc were significantly associated with lower pcs and mcs scores .
poorer mcs outcomes in patients with fractures seem to be , at least partially , associated with higher prevalence of significant subjective symptoms , like systemic symptoms and fatigue , as assessed by the pbc-40 and pbc-27 . on the other hand
, it has been suggested that fatigue does not seem to be a specific symptom in psc compared with the general population ( 26 ) . in a study by angulo
et al ( 14 ) comprising 237 participants , aged over 54 years , bmi lower than 24 kg / m and duration of ibd longer than 19 years , correlated with the presence of metabolic bone disease . on the other hand , campbell et al .
( 13 ) showed that low bone density can not be predicted by severity of liver disease in psc patients listed for liver transplantation or with hepatic decompensation .
earlier reports pointed more advanced bone disease in psc patients with end - stage liver disease evaluated for liver transplantation ( 16 ) and liver cirrhosis generally was a major risk factor of bone disease in patients evaluated for liver transplantation ( 17 ) .
however , the natural history of psc is associated with impairment in hrqol as shown by benito de valle et al . ( 26 ) and more recently by our group ( 27 ) .
age was negatively related to all sf-36 physical domain scores and physical component summary ( pcs ) score and positively to sf-36 mental health , role emotional and mental component summary ( mcs ) scores .
patients with liver cirrhosis had lower sf-36 scores of physical functioning , role functional , general health , mental health and pcs scores in comparison to non - cirrhotic individuals in benito de valle et al .
however , neither fatigue nor psychological distress was more common in psc patients compared to general population and the disease severity was not a major determinant of hrqol in unselected patients with psc ( 26 ) .
recently , we also found that female gender and older age influenced hrqol in polish cohort of psc patients ( 27 ) .
mental component summary of sf-36 was significantly lower in females than males and men generally showed better quality of life in the study with sf-36 , pbc-40 and bc-27 questionnaires ( 27 ) .
the results of the current study to the novel aspect of quality of life in psc patients , i.e. the impact of fragility bone fractures on hrqol .
we found lower scores of role physical , general health , vitality and pcs scores in respect to sf-36 questionnaire and symptoms in both pbc-40 and pbc-27 tools in psc patients with fragility osteoporotic bone fractures .
these results suggest the impairment of physical aspect of hrqol in severe osteoporosis associated with psc .  
fatigue is probably the most intriguing symptom affecting patients with chronic cholestatic disorders ( 28 ) .
it did not seem to be a specific complaint of psc in benito de vale et al .
study ( 26 ) , but al - harthy et al . found that fatigue was an important , but under reported symptom for patients with psc , particularly in female patients ( 11 ) .
ibd presence was also associated with more severe fatigue in psc patients in al - rifai et al .
however , the result of our recent study might indicate silent bone complication as a cause of this symptom .  
hence , the associations presented between independent factors and outcome variables do not necessarily represent causal relationships .
second , we studied a relatively modest sample of males and females from a single tertiary center , subjected to referral and selection bias .
additionally , males have higher bone mass than females , especially postmenopausal females . to reduce any potential bias associated with gender - specific bmd values , we did not include women after menopause and bmd was expressed in gender - specific z - scores and t - scores .
vertebral fractures are the most common form of osteoporotic fractures ( 30 ) and largely undiagnosed ( 31 ) .
moreover , vertebral fractures , common among corticosteroid users , are frequently asymptomatic or poorly symptomatic , but they substantially affect quality of life ( 32 ) .
thus , we can not exclude that undiagnosed vertebral fractures might influence hrqol outcomes in our patients .   in conclusion ,
in young and middle - aged subjects with psc lasting for approximately three years , we found a high rate of fragility , non - vertebral fractures and moderately lower bmd in the lumbar spine and hip .
fragility fractures have an impact on physical and mental aspects of hrqol , as assessed by both generic and disease - specific questionnaires .
 background : osteoporosis occurs frequently in patients with chronic cholestatic liver diseases , yet data are scarce regarding the prevalence of osteoporosis and fragility fractures and their impact on health - related quality of life ( hrqol ) in primary sclerosing cholangitis ( psc).objectives : we aimed to assess bone mineral density ( bmd ) , physical activity and incidence of fragility fractures in patients with psc . 
 we also sought associations between prior fractures and hrqol.patients and methods : the study was performed on 33 patients ( 11 females , 22 males ) aged 35.3  13 years . 
 hrqol was assessed by short form ( sf)-36 , primary biliary cirrhosis ( pbc)-40 and pbc-27 questionnaires . bmd was measured by densitometry in the lumbar spine and hip . 
 physical activity was assessed by questionnaire.results:in 32% of patients , bmd measured in the hip or spine was below 1.0 standard deviation . a history of fragility fractures ( distal forearm and ribs ) was reported in six patients ( 18% ) . in sf-36 assessment , patients with fractures had lower scores in the role functioning , general health and vitality domains and physical component summary ( pcs ) than those without fractures . 
 prior fractures adjusted for gender and psc duration were associated with lower pcs and mental component summary ( mcs ) scores . 
 symptoms and fatigue ( assessed by pbc ) and prior fractures were inversely associated with mcs ( p = 0.007).conclusions : in middle - aged subjects with psc , we found a high rate of non - vertebral fractures and a moderately decreased bmd in lumbar spine and hip . 
 fragility fractures had an impact on physical and mental aspects of hrqol . 
1. Background
2. Objectives
3. Patients and Methods 
3.1. Study Population
3.2. Bone Mineral Density Measurements 
3.3. HRQoL Assessment
3.4. Assessment of Physical Activity 
3.5. Statistical Analysis
4. Results
5. Discussion