Bone fractures in primary biliary cholangitis

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic cholestatic disease of presumed autoimmune origin, characterized by inflammation and damage to the small intrahepatic bile ducts, which eventually leads to cirrhosis and the need for liver transplantation. The disease mainly affects middle-aged women with features of chronic cholestasis, although currently most patients are asymptomatic and are characterized by some biochemical abnormalities, in particular increased alkaline phosphatase levels and the presence of antimitochondrial antibodies [1]. There are a number of manifestations associated with cholestasis, such as pruritus, which can be very severe, and the development of bone metabolic disease, usually osteoporosis, leading to an elevated risk of fracture. Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to increased bone fragility and risk of fracture. The pathogenesis of osteoporosis in PBC is multifactorial, mainly due to decreased bone formation with increased bone resorption at late stages [2]. Bile acids and bilirubin, which accumulate during cholestasis, may play a key role in this process by inducing osteoblast apoptosis and by directly stimulating osteoclast activity, as observed in some “ in vitro” studies [3]. The reported prevalence of osteoporosis in patients with PBC is highly variable, mostly depending on the diagnostic criteria and the severity of liver damage, although in the most outstanding studies, this prevalence was around 35% [2]. In one of the largest series of patients with PBC, the prevalence of osteoporosis assessed by dual-energy X-ray absorptiometry (DXA) was approximately 30%, significantly higher than that of the age-matched population. Duration of PBC greater than 4 years, age greater than 56 years, and advanced histological stage were the independent variables associated with osteoporosis. A lower prevalence of osteoporosis is observed in patients with less severe disease, whereas the prevalence is very high in advanced liver disease just before transplantation [4]. The prevalence of fractures mainly due to osteoporosis is not well established and ranges from 2% to 23% [2]. However, in patients with advanced pretransplant liver disease, the prevalence is up to 22%. In a large cohort of patients from Spain, vertebral fractures were associated with lumbar and femoral osteoporosis as well as osteopenia. The prevalence of vertebral fractures increased with the severity of cholestasis. In addition, this study identified the bone mineral density (BMD) threshold at which most vertebral fractures occur. The strong association between vertebral fractures and a T-score of less than −1.5 at the lumbar spine or femoral neck provided a cut-off value for BMD measurements that indicates a high risk of vertebral fractures in PBC patients [5]. The article by Schonau et al. [6] provides some relevant results, as it reports a clear increase in the incidence of overall fractures and osteoporotic fractures in a large series of patients with PBC compared to the general population. The results further indicate that the increased risk is even more pronounced in the subgroup of males, representing 15% of the cohort. This finding supports that osteoporosis in PBC is highly influenced by liver disease and that the contribution of menopause in women is probably only one additional factor. This study surprisingly describes a very low prevalence of osteoporosis, which stands at 3%. However, the history of fractures in the typical sites of osteoporotic fractures such as vertebrae, wrist, pelvis, and hip is extensive. These data support that osteoporosis was probably underdiagnosed in this cohort of PBC patients, as already indicated by the authors. In fact, the interest of this study lies in the incidence of fractures, not in the prevalence of osteoporosis. The estimated rate of incident fractures in PBC is not well known, as very few reports have been published on this topic. One study reported 5% incident fractures over 2 years, whereas another study reported that 13% of patients with PBC had new radiographic vertebral deformities over the same period. Other reports are conflicting, regarding the increased risk of fracture in PBC [2]. Moreover, although one study failed to demonstrate an increased fracture risk [7], another population-based cohort study of 930 patients with PBC found a modest increase in both the absolute and relative fracture risk compared to the general population [8]. The study by Schonau et al., which includes a larger cohort of patients followed over a longer period, describes an approximately twofold increased risk of any fracture, especially at the spine in patients with PBC compared to the general population. Thus, the results of this study in a Swedish population are similar to and, in part confirm, previous data from the UK PBC cohort. Furthermore, in the Swedish study, the cumulative incidence of any fracture during complete follow-up was as high as 36.3% and 26.6% at 10 years. These figures were even higher in patients with baseline osteoporosis, in whom the incidence of any fracture was as high as 49.6%, suggesting that fractures, primarily due to osteoporosis, are a major event in patients with PBC. This suggests that measures aimed at improving bone mass are essential to prevent this complication. The higher risk of death after a fracture event in PBC compared to the general population is another interesting finding of the study. PBC patients had significantly higher 30-day and 1-year mortality rates compared to the controls who also experienced a fracture. In the adjusted model, there was an approximately twofold relative increase in mortality after a fracture in PBC patients. This finding is consistent with reduced survival after an osteoporotic fracture, particularly vertebral and hip fractures, in postmenopausal women, as well as in men, and is greater in those with coexisting medical conditions [9]. Several practical points can be drawn from this study, which reports the increased incidence of fractures in patients with PBC, as well as the impact on mortality. First, that osteoporosis and osteopenia should be assessed in all patients with PBC, regardless of the severity of cholestasis, at diagnosis and especially in cases of advanced disease or prolonged cholestasis, by a noninvasive method such as measurement of BMD by DXA. Second, the drugs tested for osteoporosis in PBC have shown maintenance or increase of BMD, although they have not been proven to reduce fracture risk, probably because the trials include few patients and are limited in duration [2, 10]. Nevertheless, given the data presented in this article, it is highly advisable to identify and treat patients at increased risk of fracture, and it is mandatory for those who have already developed a first fracture. The authors declare no conflict of interests concerning this publication.