Accepted Manuscript

Bone Health in Patients with Liver Diseases

Christopher J. Danford M.D. , Hirsh D. Trivedi M.D. ,

Alan Bonder M.D.

PII: S1094-6950(18)30253-1
DOI: https://doi.org/10.1016/j.jocd.2019.01.004
Reference: JOCD 1107

To appear in: Journal of Clinical Densitometry

Received date: 4 December 2018

Revised date: 15 January 2019
Accepted date: 15 January 2019

Please cite this article as: Christopher J. Danford M.D. , Hirsh D. Trivedi M.D. , Alan Bonder M.D. ,
Bone Health in Patients with Liver Diseases, Journal of Clinical Densitometry (2019), doi:
https://doi.org/10.1016/j.jocd.2019.01.004

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 ACCEPTED MANUSCRIPT

Bone Health in Patients with Liver Diseases

Running title: Bone Health in Liver Diseases

Christopher J. Danford M.D.1, Hirsh D. Trivedi M.D.1, Alan Bonder M.D.1

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Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center,

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Harvard Medical School, Boston, MA 02215, USA

Correspondence to: US
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Alan Bonder, MD

Liver Center, 110 Francis St. Suite 8E

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Division of Gastroenterology and Hepatology

Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

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abonder@bidmc.harvard.edu

Telephone: 617-632-1070
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Fax: 617-623-1065
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Abstract

Osteoporosis is the most common bone disease in chronic liver disease resulting

in frequent fractures and leading to significant morbidity in this population. In addition to

patients with cirrhosis and chronic cholestasis, patients with chronic liver disease from

other etiologies may be affected in the absence of cirrhosis. The mechanism of

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osteoporosis in chronic liver disease varies according to etiology, but in cirrhosis and

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cholestatic liver disease it is driven primarily by decreased bone formation, which differs

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from the increased bone resorption seen in postmenopausal osteoporosis. Direct toxic

effects from iron and alcohol play a role in hemochromatosis and alcoholic liver disease,

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respectively. Chronic inflammation also has been proposed to mediate bone disease in
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viral hepatitis and nonalcoholic fatty liver disease. Treatment trials specific to

osteoporosis in chronic liver disease are small, confined to primary biliary cholangitis
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and post-transplant patients, and have not consistently demonstrated a benefit in this

population. As it stands, prevention of osteoporosis in chronic liver disease relies on the

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mitigation of risk factors such as smoking and alcohol use, treatment of underlying

hypogonadism, and encouraging a healthy diet and weight-bearing exercise. The

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primary medical intervention for the treatment of osteoporosis in chronic liver disease
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remains bisphosphonates though a benefit in terms of fracture reduction has never

been shown. This review outlines what is known regarding the pathogenesis of bone
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disease in chronic liver disease and summarizes current and emerging therapies.

Keywords: cirrhosis, cholestasis, osteoporosis, bisphosphonates

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Introduction

Metabolic bone disease is a common complication of chronic liver disease (CLD).

The term hepatic osteodystrophy is sometimes used to refer to all metabolic bone

complications seen in CLD. It refers to both osteomalacia, or decreased bone

mineralization, and osteoporosis, or decreased bone mass, which can both be seen in

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advanced liver disease. Osteomalacia was once thought to be common particularly in

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cholestatic liver disease, theoretically due to dietary vitamin D malabsorption in the

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setting of severe cholestasis and impaired hepatic 25-hydroxylation (1, 2). However, it

appears osteomalacia is actually quite rare in cholestatic liver disease and CLD in

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general and early studies were plagued by selection bias and a loose definition of
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osteomalacia (3). It is now widely accepted that osteoporosis is the primary metabolic

bone disease in primary biliary cholangitis (PBC) (4) and likely CLD in general and this
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review will focus on osteoporosis and osteopenia in CLD.

Osteoporosis is defined by the World Health Organization as bone mineral

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density (BMD) at the spine or proximal femur less than 2.5 standard deviations below

the mean of a young adult population (expressed as a T score) on dual X-ray

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absorptiometry (DEXA) (5). Osteopenia refers to those with a T score between -1.0 and
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-2.5 standard deviations below the mean. Osteoporosis is a major risk factor for

fractures (6, 7), which are especially difficult to manage in patients with advanced liver
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disease with perioperative morbidity and mortality approaching 80% and 60%

respectively in cirrhotics undergoing emergent total hip arthroplasty (8). Patients

therefore would benefit from timely diagnosis, effective risk factor modification, and

treatment of osteoporosis in CLD. This review seeks to summarize what is known

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regarding the burden of bone disease in CLD, its pathophysiology, and management.

To this end, we performed a comprehensive literature review using search terms

“cirrhosis”, “chronic liver disease”, “osteoporosis”, “osteopenia”, “hepatic

osteodystrophy” in PubMed, Web of Science, the Cochrane database, and the

Countway Library to obtain studies for inclusion in this review.

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Burden of Disease

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The prevalence of osteoporosis and fractures varies depending on the etiology of

liver disease and degree of liver dysfunction. Most data come from cholestatic liver

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disease; however, there is evidence of bone disease in most liver disorders from viral
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hepatitis to nonalcoholic fatty liver disease (NAFLD). Evidence regarding the prevalence

of osteoporosis and fractures in different liver diseases is summarized in Table 1.

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In primary biliary cholangitis (PBC; previously known as primary biliary cirrhosis),

osteoporosis prevalence nears 30% (9), but ranges from 20-45% (10–13) depending on
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the degree of liver disease with the highest prevalence among PBC patients with

cirrhosis on the liver transplant list (14). Fracture prevalence also varies from 8.5% to
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22% (7, 10, 11, 13, 15) among patients awaiting liver transplant (14). While many PBC
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patients are postmenopausal women, osteoporosis prevalence is higher than in age-

matched controls (11%) (7, 13), a phenomenon that persists even among women
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without cirrhosis.(16) Osteoporosis is also common among primary sclerosing

cholangitis (PSC) patients with prevalence ranging from 15% in a population in which

54% had cirrhosis to 32% in patients awaiting transplant (14, 17). Fracture prevalence

also increases from 6% to 16% in an entirely cirrhotic population (14, 17). Risk is also
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increased from age- and gender-matched controls and is aggravated not only by age

and low BMI, but also by long-term inflammatory bowel disease (17).

Among non-cholestatic liver disease, hereditary liver diseases such as hereditary

hemochromatosis, Wilson disease, and alpha 1 antitrypsin deficiency (A1ATD) also

likely confer increased risk of osteoporosis. Prevalence of osteoporosis in hereditary

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hemochromatosis ranges from 25-45% (18–21) with fracture prevalence of 23% (21).

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These findings are independent of hypogonadism or cirrhosis and a decrease in femoral

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neck BMD correlates with increasing hepatic iron concentrations (20). Similarly, Wilson

disease is also associated with decreased bone mineralization independent of liver

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disease severity or other osteoporosis risk factors (22). A recent meta-analysis found a
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prevalence of osteoporosis of 27.7% combining both adult and pediatric populations

with Wilson disease and a prevalence of vertebral fractures of 8% among adults (23).
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Patients with A1ATD not on chronic corticosteroids also have a higher prevalence of

osteoporosis (42%) compared to age-, gender-, and smoking-matched controls (10%)

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(24). Osteoporosis is more prevalent in patients with chronic obstructive pulmonary

disease (COPD) due to A1ATD (28.5%) compared to COPD due to smoking (20.4%)
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(25).
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Data on the effect of infection with hepatitis B virus (HBV) on bone disease is

limited. One small study including only 13 patients noted an osteoporosis prevalence of
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15%; however, there was no control group and decreased BMD was associated with

fibrosis stage on liver biopsy (26). Infection with HBV has been reported to be

associated with increased incidence of osteoporosis compared to controls (adjusted

hazard ratio 1.14 [1.03-1.25]) after adjustment for confounders such as age, sex, and
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comorbidities, though notably was not adjusted for treatment with tenofovir disoproxil

fumarate (TDF) which may decrease BMD (27, 28). Similarly risk of fracture is also

reported to be slightly elevated in those with chronic HBV infection, though this was only

significant among untreated African-American patients raising the possibility of

confounding factors (29). Data in patients with chronic hepatitis C infection (HCV) is

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also conflicting. A recent meta-analysis reported increased risk of osteoporosis (OR

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2.47, 95% CI 1.03-5.93) among HCV patients compared to controls; however, this was

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only demonstrated after removing the largest study (n = 51,535) from the analysis which

was removed since it used diagnosis codes to identify cases of HCV infection and

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osteoporosis as opposed to chart review utilized in the smaller studies which included
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only a total of 249 patients (30). In addition, the studies on which this was based did not

control for tobacco and alcohol use, treatment with interferon, and cirrhosis which can
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all decrease BMD (5, 31, 32). Among HCV patients with cirrhosis, osteoporosis

prevalence has been reported as high as 42.9% (33), though in non-cirrhotic men and
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pre-menopausal women the reported prevalence is 0% (34). Risk of fracture is

increased in HCV patients; however, HCV exposure is no longer a significant risk factor
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after multivariable analysis controlling for other markers of high-risk behavior and
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osteoporosis risk factors such as HIV infection, IV drug use, and alcohol use (35).

Fracture risk remains elevated in HCV patients who have cleared the virus indicating
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that HCV infection may be more of a marker of high-risk behavior than a cause of

osteoporosis-mediated fragility fractures (35).

Similarly, it is difficult to differentiate out whether patients with alcoholic liver

disease (ALD) are at increased risk of osteoporosis and fractures mediated through liver
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disease or simply due to malnutrition, direct toxic effect of alcohol, and risky behavior.

Chronic alcohol use is a well-established independent risk factor for decreased BMD

(36). Prevalence of osteoporosis was 34% in one study of males with chronic alcohol

use; however, this was not adjusted for degree of liver disease (37). Alcoholic patients

are also at increased risk of fractures with a 36% prevalence of vertebral fractures in

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one study (38). The majority of these patients had normal BMD, suggesting trauma or

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increased propensity to falls may play a significant role in this population (38).

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Though data is sparse, NAFLD may be associated with decreased bone density.

In a retrospective cross-sectional study of 265 post-menopausal women, NAFLD was

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independently associated with lower BMD after controlling for age, body mass index,
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ALT, tobacco, alcohol use, and the presence of metabolic syndrome (39). These

findings were not seen in patients with simple steatosis, suggesting that nonalcoholic
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steatohepatitis (NASH) and chronic subclinical inflammation may contribute to the

underlying pathophysiological mechanisms (40, 41). Obese children with NASH also
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have lower BMD than both obese children with non-NASH NAFLD and obese controls

(42). Men with NAFLD are at increased risk of fractures as well after controlling for risk
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factors, though these results were not seen in women (43).

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Patients with autoimmune hepatitis (AIH) on maintenance corticosteroids are at

increased risk of osteoporosis, however, data on AIH in the absence of long-term

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steroid use is lacking (44).

Regardless of etiology, cirrhosis itself is a well-established risk factor for

osteoporosis with prevalence ranging from 20-43% (45–48). The prevalence of fractures

in patients awaiting liver transplant ranges from 7-33% (45, 49, 50). Post-transplant,
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most patients experience further decrease in BMD of 8-18% in the first 3-6 months post-

transplant (51–53) with very high incidence of fractures (20-38%) in the first year post-

transplant (52, 54–56). After 1 year, however, BMD returns to pre-transplant baseline

and may improve even in cholestatic liver disease (51, 52).

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Pathogenesis

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Study of the pathogenesis of osteoporosis in chronic liver disease has largely

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focused on PBC, though the mechanism likely overlaps in the case of end stage liver

disease from other etiologies due to cholestasis. The pathogenesis of osteoporosis in

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PBC appears to be largely driven by decreased bone formation, though increased bone
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resorption may play a role in certain scenarios. Several studies evaluating bone

histomorphometry have shown decreased tetracycline double-labeling, bone formation

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rates, osteoblast numbers, and serum osteocalcin, pointing towards osteoblast

dysfunction and deficient bone formation as central to the pathogenesis of PBC-related

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osteoporosis (6, 57–59).

Osteoblast dysfunction is a multifactorial process caused both by decreased

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osteoblastogenesis and increased osteoblast apoptosis. Serum levels of insulin-like

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growth factor-1 (IGF-1) and vitamin K, which both stimulate osteoblastogenesis, may be

decreased (60, 61). Elevated levels of bilirubin, bile salts, and altered fibronectin
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production may also play a role in decreased bone formation through inhibition of

osteoblastogenesis and osteoblast activity (62–64). Sclerostin, a Wnt antagonist that

inhibits osteoblastogenesis, is increased in patients with PBC (65).

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Increased bone resorption may also play a role in osteoporosis in PBC in certain

populations such as post-menopausal women and men with hypogonadism (3, 6, 57).

One study showed increased osteoblast numbers and increased eroded surface area

indicative of increased resorption, but only in female patients with cholestatic liver

disease (57). Men with cholestatic liver disease show no signs of increased bone

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resorption despite similar degrees of osteopenia (57). These findings were not

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correlated with estrogen levels or menopausal state, thus the reason for bone resorption

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in women with PBC remains unclear. Figure 1 illustrates the proposed mechanism of

osteoporosis in cholestatic liver disease which is primarily due to decreased bone

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formation in contrast to postmenopausal osteoporosis.
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Theoretically, calcium and vitamin D deficiencies may develop in those with

cholestatic liver disease leading to secondary hyperparathyroidism and increased bone

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resorption. Data is conflicting, however. Some studies have found decreased calcium

absorption and serum vitamin D levels in PBC patients compared to controls (6, 66), but
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others have found normal vitamin D, calcium, and PTH levels even among osteoporotic

patients with PBC (57, 58, 64). In addition, vitamin D supplementation to normal levels
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has not been shown to improve bone mineral density BMD in PBC.(67, 68) While
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vitamin D absorption may be impaired in those taking cholestyramine, this is overcome

by increasing the oral dose of vitamin D (68).

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A systemic inflammatory state may play a role in increased osteoporosis in viral

hepatitis and NASH. TNFα is a potent bone-resorbing agent that stimulates

osteoclastogenesis (69). Serum concentrations of soluble TNF receptor are higher in

patients with osteoporosis and cirrhosis from viral hepatitis compared to those without
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osteoporosis (70). TNFα levels are also elevated in NASH (71). Though this has not

been specifically correlated with osteoporosis, NASH appears to carry an increased risk

of bone disease while simple steatosis does not (40, 42).

Hypogonadism leads to increased bone resorption in hemochromatosis and

alcoholic liver disease (21, 72). In addition, bone disease is independent of

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hypogonadism and both alcohol and iron have direct effects on bone formation and lead

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to decreased osteoblast activity (72, 73).

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Mechanical skeletal loading stimulates increased bone mineral density by

inhibiting bone resorption and increasing bone formation (74). Increased physical

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activity improves bone density in post-menopausal women (75). Decreased physical
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activity may play a role in osteoporosis in NASH (41), cirrhosis, and acutely post-

transplant(56), but has not been specifically studied. Obesity generally is considered a
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protective factor against osteoporosis (5). In the case of NASH, however, this may be

counteracted by subclinical inflammation (71) and physical inactivity (41).

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Treatment with medications specific to the underlying liver disease may also

affect BMD as in the case of TDF in HBV (28), interferon or ribavirin in HBV and HCV
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(31), and corticosteroids in AIH (44). Post-transplant immunosuppression also plays a

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major role in the early decline in BMD after transplant (76). While not a major driver of

bone disease prior to transplantation, bone resorption increases acutely after transplant
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(52). This increased bone resorption is largely attributable to glucocorticoids which

increase levels of the receptor activator of nuclear factor-κB ligand (RANKL) promoting

osteoclastogenesis and inhibiting intestinal absorption and renal reabsorption of calcium

(77). The degree of bone loss is correlated with cumulative glucocorticoid dose (78).
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Calcineurin inhibitors such as tacrolimus and cyclosporine prevent calcium reabsorption

in the distal convoluted tubule and inhibit expression of the vitamin D receptor at the

mRNA level (79). Reports on the effect of calcineurin inhibitors on bone loss in humans

post-transplant are conflicting and difficult to separate from the effect of glucocorticoids

(76). However, in the absence of ongoing glucocorticoid use, BMD recovers by 1 year

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post-transplant despite ongoing use of calcineurin inhibitors and the independent

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contribution of these medications may not be clinically significant (51, 52, 78).

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Management

Prevention US
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General measures to prevent bone loss in liver disease are extrapolated from

osteoporosis risk factors in the general population. Epidemiologic data suggests lifestyle
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factors such as tobacco and alcohol use, low dietary calcium intake, and low levels of

exercise are associated with decreased bone density and fracture risk (5). Based on
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this, we recommend tobacco and alcohol cessation, routine weight-bearing exercise,

and a balanced diet in all patients with liver disease (9). General recommendations for
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daily dietary calcium and vitamin D intake in at-risk populations are 1200 mg and 800 IU
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daily, respectively (5). Patients with cirrhosis, malnutrition, and decreased appetite may

require supplementation to achieve these goals. Patients on TDF for hepatitis B should
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be switched to tenofovir alafenamide whose improved stability permits 90% lower

plasma concentrations of tenofovir and reduces bone toxicity (80, 81). Figure 2

summarizes our strategy for prevention of bone disease in liver patients based on their

underlying pathophysiology.
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Treatment

Timing of treatment is based on recommendations from the literature on

postmenopausal osteoporosis (82). Treatment should be initiated in all patients with

osteoporosis (T score < -2.5). The ideal time to start treatment in those with osteopenia

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(T score < -1 to -2.5) is less well established. The National Osteoporosis Foundation

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recommends treatment in individuals with a prior hip or vertebral fracture or 10-year hip

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fracture risk ≥ 3% or osteoporosis-related fracture risk ≥ 20% based on the World

Health Organization Fracture Risk Assessment Tool (FRAX) in those with osteopenia

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(82). At least in PBC, patients with a T score < 1.5 appear to be at increased risk of
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vertebral fracture (7) and initiation of treatment could be considered at this point. Given

expected bone loss of 8-18% in the first 3-6 months post-transplant (51, 52, 78) and
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very high incidence of fractures (20-38%) in the first year post-transplant (52, 54–56),

one could consider treating osteopenia (T score < -1) in patients on the liver transplant
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waitlist. One retrospective study examined treatment of osteopenia with ibandronate

prior to transplant and noted improvement in BMD and only one fracture (3.2%) 12
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months post-transplant, however, prospective studies are required before more solid
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recommendations can be made (83). The duration of treatment is unclear even in the

postmenopausal population, though the National Osteoporosis Foundation emphasizes

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that treatment should not be indefinite and generally is continued for anywhere from 2 to

5 years based on individual risk assessment (82).

Vitamin D and calcium supplementation

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In PBC patients with osteopenia or osteoporosis, vitamin D and calcium

supplementation has not been shown to improve BMD or reduce fracture risk. However,

considering the favorable safety profile of vitamin D supplements and increased risk of

vitamin D deficiency in this population, supplementation is generally recommended (3,

9, 84). The only randomized controlled trial (RCT) investigating calcitriol

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supplementation did not find a significant improvement in BMD from baseline at one

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year, though BMD did significantly worsen in those who received no treatment (85).

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Most studies use some combination of calcium and vitamin D supplementation as

standard of care in both the intervention and control groups, though notably, BMD

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continues to worsen in the control group despite supplementation (86–88).
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Bisphosphonates
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Bisphosphonates reduce bone resorption and are effective in increasing BMD

while reducing fractures in postmenopausal osteoporosis (89). Their effectiveness in

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chronic liver disease is not as clear due to the small number of studies with small study

size and short follow-up. A 2011 Cochrane review of bisphosphonates in PBC

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concluded there was insufficient data supporting improved BMD and decreased fracture
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risk (90). It appears etidronate, a non-nitrogen-containing bisphosphonate, is not

effective in improving BMD and preventing fractures in PBC. In two RCTs comparing
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etidronate to calcium alone or placebo, neither demonstrated an improvement in BMD

from baseline or difference in fracture risk (91, 92).

Alendronate and other more potent nitrogen-containing bisphosphonates such as

ibandronate, pamidronate, and zolendronate have had more promising results, though
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results are mixed in terms of improvement in BMD and none have shown a fracture risk

reduction. Only one RCT has been performed comparing alendronate to placebo in

PBC (93). After 1 year, patients in the alendronate arm experienced a 10.4% increase in

lumbar spine BMD compared to -0.12% for placebo (93). There was no difference in

fracture incidence over one year (93). In trials comparing bisphosphonates in PBC,

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etidronate was shown to be inferior to alendronate (94), while ibandronate was

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equivalent to alendronate with both resulting in BMD improvement (95).

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Post-transplant, pamidronate did not improve fracture risk or BMD compared to

placebo, though this study had both lower fracture rates and less bone loss compared

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to previously published literature (96). Subsequent studies have shown improvement in
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lumbar BMD compared to placebo, but no difference in femoral BMD or fracture risk

after treatment with pamidronate (97, 98). Treatment with zolendronate resulted in
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significantly less bone loss at 3 months, though this was not sustained at 12 months

and there was no difference in fracture risk (99).

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Despite concerns for use of bisphosphonates in chronic liver disease, serious

adverse events have not been reported (93–95).

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While generally recommended as first-line treatment for osteoporosis in PBC

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(84), evidence for the efficacy of bisphosphonates in both PBC and post-transplant is

limited. Similarly powered trials in postmenopausal osteoporosis have shown

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improvement benefit in terms of both fracture reduction and BMD improvement (100),

and the true benefit of bisphosphonates in chronic liver disease remains unclear.

However, until more definitive data arises, we recommend use of nitrogen-containing

bisphosphonates as first-line therapy in chronic liver disease patients with osteoporosis.

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Hormone replacement

Estrogens have strong anti-resorptive effect on bones and for a period of time

were widely used in postmenopausal osteoporosis (101). Concerns over worsening of

cholestasis initially limited their use in chronic liver disease. However, several

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observational studies in PBC did not show any significant worsening in liver disease

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with hormone replacement therapy (HRT) (102, 103) and two subsequent RCTs

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similarly found no worsening in liver disease (86, 104). In these RCTs, those

randomized to transdermal estrogen and progesterone had less femoral and vertebral

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bone loss compared to controls after 1-2 years of treatment, though neither showed a
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reduction in fracture risk (86, 104). In addition, both studies noted an increase in

noncholestatic adverse events, such as vaginal bleeding and headaches, in the HRT
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arm leading to increased dropout (86, 104). Hormone replacement is also associated

with increased risk of venous thromboembolism, stroke, ischemic heart disease, and
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breast cancer and is not recommended in women older than age 60 or greater than 10

years after menopause (105). Hormone replacement may be effective in improving

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BMD in PBC, though no improvement in fracture risk has been shown and side effects
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limit their use. Given other options with fewer side effects, we do not recommend use of

HRT for treatment of osteoporosis in patients with chronic liver disease in the absence
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of primary hypogonadism.

Little data exists regarding use of HRT outside of PBC, though testosterone

replacement has been used in hypogonadal men with hemochromatosis (106). In this

study, 6 hypogonadal men with hemochromatosis received intramuscular testosterone

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every 3 weeks for 24 months with improvement in lumbar and forearm BMD (106).

Though the control group was eugonadal with significantly higher BMD and fractures

were not recorded, it is reasonable toscreen for and treat hypogonadism especially in

high risk groups such as hemochromatosis, alcoholic liver disease, and cirrhosis.

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Other treatment

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A number of other treatments such as sodium fluoride, calcitonin, raloxifene,

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vitamin K, and vitamin D supplementation have been evaluated primarily in the PBC

population, however, trials have been small, poorly designed, or did not show any

improvement in BMD. US
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Human parathyroid hormone (PTH) has not been studied in humans with PBC,

though it improves BMD and reduces fractures in postmenopausal osteoporosis through

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stimulating bone formation, the major driver of osteoporosis in PBC (107, 108). The

recombinant form consisting of the bioactive portion of the hormone (teriparatide) is

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approved for treatment of postmenopausal osteoporosis. Recombinant human PTH 1-

34 (rhPTH 1-34) improves BMD in rats that have undergone biliary ductal ligation (109),
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but has not been studied specifically in humans with chronic liver disease.
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Liver-specific therapies
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Efficacy of therapies directed at the underlying liver disease depends on the

etiology. Treatment of PBC with ursodeoxycholic acid or obeticholic acid, for example,

does not improve BMD or reduce fracture risk (110, 111). Abstention from alcohol, on

the other hand, does improve BMD (112). Treatment of hypogonadism and iron
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overload with testosterone replacement and phlebotomy was effective in improving

BMD in a small study of six hypogonadal men with hemochromatosis (106). In contrast,

penicillamine was not effective in improving BMD in children with Wilson disease (113).

Except for the early post-transplant period, liver transplantation also improves BMD in

the long run (51, 52, 78).

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Conclusions

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Osteoporosis is the most common bone disease in patients with CLD and affects

patients not just with cholestatic liver disease and cirrhosis, but also CLD from other

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etiologies even in the absence of cirrhosis. As opposed to post-menopausal
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osteoporosis, osteoporosis in cholestatic liver disease and cirrhosis is primarily due to

decreased bone formation. In other forms of CLD, chronic inflammation, direct toxic
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effects in the case of alcohol and hemochromatosis, or liver-related medications may

play a role. No treatment has been shown to reduce fracture risk in patients with chronic
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liver disease, though bisphosphonates may improve BMD in PBC and post-transplant.

Bisphosphonates are primarily anti-resorptive and may not treat the underlying
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mechanism of osteoporosis in cirrhosis and cholestatic liver disease. Future studies

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should evaluate anabolic bone agents such as recombinant PTH.

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Table 1. Summary of studies evaluating prevalence of osteoporosis and fractures in different types of chronic

liver disease

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Etiology Study N Femal Age Post- Cirrhosi Definition of Osteoporosi Fracture
e (%) (years menopausa s (%) osteoporosis s Prevalence Prevalenc
) l (% of (%) e (%)
women)
PBC
Guañabens 1994

Menon 2001
38

17
6
100

83
51

53
US 63

45
94 T score < -
2.5
59 T score < -
2.5
45

20
13

8.5
AN
Newton 2001 27 94 62 64 54 T score < - 31 NR
2 2.5
Parés 2001 61 100 54 79 26 T score < - 19 13
2.5
Guañabens 2005 14 100 54 69 26 T score < - 32 21
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2 2.5
Guichelaar 2006 14 86 53 68 100 T score < - 44 22
2 2.5
Guañabens 2010 18 100 56 82 23 T score < - 37 21
ED

5 2.5
Seki 2017 12 100 61 100 0 BMD 70% 26 NR
8 below young
adult mean
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BMD
PSC Guichelaar 2006 20 41 47 68 100 T score < - 33 16
4 2.5
Angulo 2011 23 42 46 40 54 T score < - 15 6
CE

7 2.5
ESLD Ninkovic 2001 24 47 51 73 100 T score < - 37 NR
3 2.5
AC
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IP
Carey 2003 20 37 51 49 100 T score < - 20 24
7 2.5
Floreani 2001 23 0 48 0 100 T score < - 52 NR

CR
2.5
Gonzalez-Calvin 84 100 65 100 100 T score < - 43 NR
2009 2.5
Alcoho Peris 1992 32 0 47 0 32 T score < - 34 NR
l 2.0

HH
Peris 1995

Kim 2003

Diamond 1989
76

18

22
0

0
47

50

49
0

0
US 8 T score < -
2.0
0 T score < -
2.5
NR T score < -
29

22

45
35

NR

23
AN
2.0 or lumbar
BMD < 98
mg/cm3

Sinigaglia 1997 32 12 NR NR 53 T score < - 28 NR

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2.5
Guggenbuhl 38 0 47 0 T score < - 34
2005 2.5
87 20 51 47 33 T score < - 25
ED

Valenti 2009 2.5 NR

A1ATD Duckers 2010 19 37 59 NR 0 T score < - 42 NR
2.5
PT

Ringbaek 2014 23 45 57 NR NR ICD-10 code 29 NR

4
CE

Wilson Hegedus 2002 21 43 31 NR NR Z score < - 43 5

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2.0

CR
Quemeneur 2014 85 55 35 7 Z score < - 13 51
NR 2.0

Weiss 2015 14 61 36 NR
US 38 T score < - 9 NR
AN
8 2.5
M

HCV Schiefke 2005 30 80 18 T score < - 20

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49 NR 2.5 NR
Raslan 2010 30 40 NR 47 T score < - 43
NR 2.5 NR
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Lin 2012 69 59 54 78 0 T score < - 7

2.5 3
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Orsini 2013 60 0 41 0 0 Z score < - 1 (age < 50) 2

2.0 (age < 36 (age >
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Schiefke 2005 13 54 49 NR 18 T score < - 15 NR

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HBV 2.5

PBC, primary biliary cholangitis; BMI, body mass index; NR, not reported; BMD, bone mineral density; PSC, primary

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sclerosing cholangitis; ESLD, end-stage liver disease (composite of all etiologies with cirrhosis); HH, hereditary

hemochromatosis; A1ATD, alpha-1 antitrypsin deficiency; COPD, chronic obstructive pulmonary disease; HCV, hepatitis

C virus; HBV, hepatitis B virus

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Figure Legends

Figure 1. A proposed mechanism of osteoporosis in cholestatic liver disease.

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Figure 1 Legend. Osteoporosis in cholestatic liver disease develops largely from

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reduced bone formation. Decreased IGF-1 and vitamin K lead to decreased osteoblast
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stimulation while increased bilirubin, bile salts, sclerostin, and the oncofetal domain of

fibronectin result in increased osteoblast inhibition. In postmenopausal PBC patients,

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decreased estrogen also leads to increased bone resorption, which is the primary

mechanism in postmenopausal osteoporosis.

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Figure 2. Schematic demonstrating factors contributing to the development

osteoporosis in chronic liver disease, potential preventive interventions, and treatment

of osteoporosis.

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Figure 2 Legend. Numerous factors (ovals) contribute to the development of

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osteoporosis in chronic liver disease and are specific to different etiologies.

Interventions (arrows) to prevent the development of osteoporosis also vary by etiology.

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Liver transplantation improves bone mineral density in the long-term, though low bone
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mineral density alone is not an indication for transplant. Weight-bearing exercise should

be encouraged in NASH and early physical therapy in those with frailty due to cirrhosis

and post-transplant. Calcium and vitamin D as well as nutritional supplementation may

be necessary in those with poor nutritional intake. Abstinence from alcohol should be

encouraged and phlebotomy should be used in hereditary hemochromatosis.

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Alternatives to medications that lower bone mineral density should be considered and

hypogonadism should be addressed. In those with osteoporosis, bisphosphonates are

recommended as first-line therapy, though consideration should be given to PTH-

agonists in those with cirrhosis and cholestatic liver disease as this may more

adequately address decreased bone formation seen in these conditions. Treatment can

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be considered in those with a bone mineral density T score < -1.5 in PBC or < -1.0 pre-

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transplant as these populations are also at increased risk of fracture, though further

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study is needed to demonstrate a benefit. PBC, primary biliary cholangitis; PSC, primary

sclerosing cholangitis; BMI, body mass index; TDF, tenofovir disoproxil fumarate; PTH,

parathyroid hormone US
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