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 .