Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by intrahepatic non-purulent destruction of the small bile ducts[1]. Inflammation of the bile ducts and progressive absence of the bile ducts cause cholestasis, which can cause calcium and vitamin D malabsorption, hyperbilirubinemia, impair osteoblastic function, reduce bone formation, and lead to osteoporosis [2].
Osteoporosis (OP) is a common systemic bone disorder characterized by low bone mass, increased bone fragility, and increased risk of fractures. OP can occur at any age, but is more common in postmenopausal women and older men. Osteoporotic fractures are one of the main causes of disability and death in elderly patients, so OP should be diagnosed and prevented as soon as possible to reduce the occurrence of fractures [3].
The study [4] found that compared with normal peers, the risk of osteopenia and osteoporosis in patients with PBC is greater, and opatia increases the incidence of fractures and the risk of case fatality in patients with PBC, so it is necessary for clinical patients with PBC to routinely and regularly check bone density, prevent and treat osteoporosis as soon as possible, avoid or reduce the occurrence of fractures, and improve the quality of life of patients with PBC.
1 Epidemiology
Previous studies [4] have found a prevalence of 20% to 52% of patients with PBC with OP, 7% to 14% of fractures, up to 20% in advanced stages, and 22% in patients awaiting liver transplantation. The latest PBC guidelines, published by the American Society for the Study of Liver Diseases (AASLD) in 2018, indicate that patients with PBC have a significantly higher risk of osteopenia and osteoporosis compared to age- and sex-matched control groups [5] and are three times more likely to develop osteoporosis than the general population [6]. At the same time, PBC is more common in women over 60 years of age [7], and menopause is an important risk factor for osteoporosis, and the risk of osteoporosis in postmenopausal women with PBC is significantly increased. The incidence of osteoporosis in patients with PBC increases with disease progression, most patients with advanced PBC have varying degrees of bone disease [8], patients with post-liver transplantation are more likely to develop OP, and the use of immunosuppressants after liver transplantation can exacerbate osteoporosis [9].
The annual incidence and prevalence of PBC are 8.55 cases/1 million and 191.18 cases/1 million cases, respectively [7], and as the level of PBC diagnosis increases, there will be a large number of potentially high-risk osteoporosis patients. Therefore, it is particularly important to identify high-risk groups with OP, give timely diagnosis and reasonable treatment.
2Etiology and pathogenesis
Osteoporosis is caused by an imbalance in the activity of osteoblasts and osteoclasts. When the balance between osteocytes and osteoclasts is disrupted, bone resorption occurs faster than bone formation, bone mass decreases, osteoporosis progresses. Studies evaluating bone tissue morphology [10] have shown a decrease in tetracycline bilabeling, a decrease in bone formation rate, a decrease in osteoblast number, and serum osteocalcin in patients with PBC, indicating that osteoblast dysfunction and osteogenesis deficiency are at the heart of the pathogenesis of PBC combined with OP.
Osteoblast dysfunction is a multifactorial process caused by decreased osteoblast production and increased apoptosis. Decreased levels of insulin-like growth factor-1 and vitamin K in serum stimulating osteoblast production, elevated levels of bilirubin and bile salts, and altered fibrine production may lead to decreased bone formation by inhibiting osteoblast production and osteoblast activity [10-12].
Cholestasis in patients with PBC can cause elevated stone bile acid and bilirubin, reduce the expression of some bone morphogenetic proteins (BMP), downregulate the expression of osteoblasts (Runx2), weaken the activity, differentiation, and mineralization of osteoblasts, increase apoptosis of osteoblasts, and reduce osteoblast formation [13].
Nuclear factor-κB receptor activator ligand (RANKL) is a soluble protein secreted by osteoblasts that binds to nuclear factor-κB receptor activation factor (RANK) on the surface of osteoclasts to stimulate osteoclast differentiation and inhibit osteoclast apoptosis [14]. Osteoprotein (OPG) acts as a free receptor to bind to RANKL, preventing RANKL from binding to RANK and inhibiting osteoclast activity [15]. Studies [16] found that elevated OPG levels and decreased RANKL levels in patients with PBC indicate OPG compensatory antagonism to RANKL when osteoclasts are activated, and increased bone resorption in patients with PBC can be known.
In addition, postmenopausal estrogen levels in female patients decreased, the role of estrogen in inhibiting osteoclasts weakened, and osteoclast function was enhanced, promoting bone resorption [17]. PBC patients are more common in middle-aged and older women, and decreased estrogen levels may be one of the main reasons for the higher prevalence of combined OP in patients with PBC.
PBC is an autoimmune liver disease with a distinct genetic predisposition. Studies [18] have found that the occurrence of OP and PBC may have a common genetic susceptibility gene. Genome-wide association analysis studies have found that TNFSF11 gene and MAPT gene are related to both PBC and bone density [19]. In addition, Professor Ma Xiong's team[20] of Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine found that the new PBC susceptibility gene rs170183 had a strong correlation with bone density based on the domestic PBC cohort and two European genome-wide association analysis databases (n=10 229). This gene variant may help elucidate the mechanism of PBC and OP co-expression, and further study of the genetic structure of PBC is needed.
PBC patients with OP are the result of a combination of factors, decreased bone formation and increased bone resorption are not isolated, and the role of genetic and genetic factors is not clear, and further research is still needed.
3 Diagnosis and treatment status
At present, there is no clear diagnostic criteria for PBC combined with OP, and most studies define it as: clinically confirmed PBC and meet the diagnostic criteria of OP. The OP diagnostic criteria are based on internationally recognized dual-energy X-ray absorption bone density measurements [3]. For postmenopausal women, men 50 years of age and older, bone density level judgment is usually expressed as t-value, T-value = (measured value - peak bone density of normal young people of the same race and same sex) / standard deviation of peak bone density of normal young people of the same race and same sex. In osteoporosis, the reduction in peak bone will reach or exceed 2.5 standard deviations (T-value≤-2.5 SD).
In addition, attention should also be paid to identifying risk factors for osteoporosis in patients with PBC, including severe cholestasis, alcohol abuse, smoking, BMI below 19 kg/m2, early menopause (in women under 45 years of age), secondary amenorrhea for more than 6 months, family history of fragility fractures, and history of glucocorticoid therapy (5 mg of prednisone for more than 3 months). Among them, for patients with severe cholestasis, due to bile stasis, the absorption of vitamin D and calcium in the intestine is reduced, secondary hyperparathyroidism and bone resorption are increased, and the occurrence of bone disease in PBC patients is induced or promoted, and serum calcium, vitamin D and parathyroid hormone levels need to be screened annually.
Bone density should be measured as soon as the diagnosis of PBC is confirmed, and prevention of osteoporosis may be initiated in patients with normal initial bone density, with regular monitoring of bone density every 2 to 3 years [5]. Osteoporosis patients who have already suffered fragile fractures should be treated aggressively to reduce the risk of further fractures [3]. Guañabens et al. [21] Through follow-up observation of 185 patients with PBC, it was found that lumbar spine T-value <-1.5 (OR=8.27) and femoral neck T-value <-1.5 (OR=6.83) were important risk factors for vertebral fractures. Therefore, when the T-value <-1.5, the risk of fracture is higher in patients, and measures should be considered to actively prevent osteoporosis.
There is currently no uniformly accepted protocol for the treatment of patients with PBC and OP, and most of the treatment experience comes from postmenopausal OP studies. Prevention and treatment should be carried out in many ways, including eliminating risk factors, preventing osteoporosis, and treating PBC. Commonly used OP treatment and prevention includes basic therapy and drug therapy such as bisphosphonates.
To prevent PBC patients with OP, it is first necessary to control and try to avoid risk factors for osteoporosis, such as encouraging alcohol withdrawal and smoking cessation. Studies [22] suggest that long-term exercise in postmenopausal women improves bone density, so patients can engage in as much physical activity and exercise as possible to improve spinal function [3].
At the same time, according to the European Society of Liver Disease Clinical Practice Guidelines for Chronic Liver Disease Nutrition [23], patients with advanced liver disease often have loss of appetite and malnutrition, so balanced nutritional support should be given to prevent malnutrition in patients with PBC. Although nutritional support does not have a clear anti-fracture effect, nutritional factors should be considered during treatment to restore or maintain nutritional status. Overall, early recognition and treatment of malnutrition has the potential to lead to better disease outcomes and prevention of complications such as osteoporosis.
Vitamin D deficiency is widespread in patients with PBC. Decreased vitamin D levels may indicate disease progression in PBC, so patients with PBC need to have serum vitamin D levels measured regularly and given vitamin D supplementation [24]. The American Endocrinological Society recommends that postmenopausal women should receive routine calcium and vitamin D supplementation[25], and that total calcium intake should be 1,000 to 1,500 mg per day, depending on age and other factors [26]. The 2018 AASLD PBC guidelines recommend daily calcium supplementation of 1,500 mg and vitamin D 1,000 IU in all perimenopausal and menopausal PBC women without a history of kidney stones [6]. The guidelines for the diagnosis and treatment of primary osteoporosis in China indicate that the recommended daily calcium intake for people aged 50 years and older is 1000 to 1200 mg, and the dose of vitamin D for OP prevention and treatment can be 800 to 1200 IU/day [3]. A five-year clinical study [27] routine calcium and vitamin D supplementation in female patients with PBC found that patients with adequate calcium and vitamin D had similar bone metabolism to women of the same age.
Ursodeoxycholic acid (UDCA) is recommended by international guidelines as a safe and effective drug for the treatment of PBC. Once patients with PBC are diagnosed, UDCA is started. UDCA can promote the secretion of bile and improve liver biochemical indicators in patients with PBC. In several studies [2, 11], it has been known that UDCA can weaken the downregulation of BMPs and Runx2 caused by stone choleric acid and bilirubin, promote the differentiation and mineralization of osteoblasts, increase the survival rate of osteoblasts, neutralize the adverse effects of bilirubin and stone bile acid on osteoblasts, and alleviate osteoporosis in patients with PBC.
For patients with poor UDCA response to PBC, fibrates or obequicholic acid (OCA) may be added. Fibrates may have a role in promoting osteoblasts [28-30], but there are currently no clinical studies of UDCA combined with fibrates in the treatment of patients with PBC with OP, and the efficacy of osteoporosis in patients with PBC is still unclear. In addition, in a Phase III clinical trial of OCA for PBC [31], no positive effect of OCA on osteoporosis in patients with PBC was found. Therefore, the prevention and therapeutic effect of PBC treatment drugs on osteoporosis still needs to be further studied and clarified.
Bisphosphonate is an anti-bone resorption agent that increases bone mass and reduces the incidence of postmenopausal osteoporosis fractures. The efficacy of bisphosphonates in patients with PBC is currently controversial. A study [32] involving six randomized controlled trials of 207 patients with PBC evaluated the efficacy of bisphosphonates on OP in patients with PBC, and the results showed that the efficacy of bisphosphonates in osteoporosis in patients with PBC was unclear, and suggested the need for more randomized clinical trials to assess the effect of bisphosphonate therapy with OP on the associated prognosis in patients with PBC.
In several studies [4, 33] in which sodium alendronate intervened in the treatment of patients with PBC, sodium alendronate was found to significantly improve bone density in patients with PBC, but the number of patients included in these studies was small, and their conclusions need to be validated by larger studies.
At the same time, we should be wary of possible gastrointestinal adverse reactions caused by oral bisphosphonates. Studies [34] suggest that patients with PBC with GASTRO disease should take bisphosphonates with caution, as oral bisphosphonates may increase the risk of gastritis or esophagitis, resulting in gastrointestinal surface erosion and bleeding. Therefore, patients with PBC should carefully choose bisphosphonate therapy according to their own gastrointestinal conditions to prevent adverse reactions.
HRT is effective in preventing bone loss and is often used in the treatment of osteoporosis in postmenopausal women. A randomized controlled study [35] involving 18 postmenopausal women with PBC who received dermal hormone replacement therapy plus vitamin D and calcium for up to two years found significant increases in bone density in the lumbar spine (P<0.05) and femoral neck (P<0.05) in the treatment group, and it was known that percutaneous hormone replacement therapy may increase bone density in PBC patients.
Raloxifene is a second-generation selective estrogen receptor modulator that acts in the bones as an estrogen agonist, reducing bone resorption and bone conversion, thereby increasing bone density. Seven postmenopausal PBC women were included who received raloxifene 60 mg/day, and lumbar bone density improved after one year (0.72 g/cm2 before treatment; 0.74 g/cm2, P=0.02) after treatment), suggesting that raloxifene was effective in preventing bone loss in patients with PBC.
There is still a great controversy about the adverse reactions of HRT. Although it is effective in reducing bone resorption, its safety remains to be clarified.
Parathyroid hormone stimulates bone formation and is effective for simple OP. Calcitonin inhibits bone resorption and is clinically used to prevent bone necrosis. Sodium fluoride prevents bone loss in patients with PBC. However, the effect of parathyroid hormone, calcitonin, sodium fluoride, etc. on osteoporosis in PBC patients and its safety are still unclear.
Dinozumab is a fully humanized anti-RANKL monoclonal antibody whose therapeutic effect is based on its ability to inhibit osteoclast differentiation [37]. The American Endocrinology Society recommends dinomab as a first-line treatment for patients at high risk of fracture and those who are unable to use oral therapy. In one study [38], long-term dinozumab therapy was found to significantly increase bone density in patients with autoimmune liver disease without any adverse effects. From this point of view, dinomab is expected to play an important role in the treatment of osteoporosis in PBC patients.
In a systematic review of 11 randomized studies and a meta-analysis of 584 patients with PBC[39], multiple treatments for osteoporosis in patients with PBC, including bisphosphonates, hormone replacement therapy, UDCA, calcitriol, and sodium fluoride, were evaluated, and none of them was supported by high-quality evidence. Most of the current drugs only focus on OP, and the drug effect is mainly in the inhibition of bone resorption, and does not target the key link of PBC combined with OP formation, that is, the reduction of bone formation. Future drug studies could target anabolic bone agents to better treat osteoporosis in patients with PBC.
4 Summary and Outlook
As people's life expectancy increases and treatment of chronic liver disease advances, the importance of managing osteoporosis and other bone diseases in patients with chronic liver disease is expected to increase. In recent years, there have been few clinical studies of patients with PBC with OP, and large-scale, multicenter randomized controlled studies are needed to obtain higher-level clinical evidence. As a high incidence of chronic liver disease with OP, once a fracture occurs, it not only seriously affects the quality of life of patients, but also increases the patient's economic burden and case fatality rate, so it is of great significance to identify risk factors for osteoporosis and prevent OP. The lack of effective preventive measures and treatment strategies remains the biggest challenge for osteoporosis in patients with PBC. More basic and clinical studies of the PBC population are needed in the future to clarify their pathogenesis and prevention and treatment options.
View the bibliography or download the full-text PDF for free
http://www.lcgdbzz.org/cn/article/doi/10.3969/j.issn.1001-5256.2021.10.004
Cite this article
ZHANG Wen,CHEN Shuyan,LV Tingting,et al. Diagnosis and treatment of primary biliary cholangitis complicated with osteoporosis[J]. Journal of Clinical Hepatobiliary Diseases, 2021, 37(10): 2272-2276.
Editor of this article: Wang Yanan
Public account editor: Xing Xiangyu
The first | of the whole network is the "Journal of Clinical Hepatobiliary Diseases" No. 10, 2021 " Basic and Clinical " Key Number of Primary Biliary Cholangitis " (Executive Editor: Han Ying)
Review | Han Ying: Diagnosis and treatment of primary biliary cholangitis and challenges
Expert Forum | Fei Yunyun: The relationship between primary biliary cholangitis and Sjögren syndrome
Expert Forum | Zhou Xinmin: Research progress related to changes in the central nervous system in patients with primary biliary cholangitis