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Bone Loss in Liver Disease
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Hepatic osteodystrophy
Hepatology; January 2001 - Volume 33 - Number 1
This interesting article discusses the risk factors associated with bone loss
in persons with liver disease. The authors suggest advancing liver disease is
associated with bone loss so improved disease progression may improve bone
loss. Additional risk factors include chronic alcohol use, tobacco use, a
decline in circulating estrogen, corticosteroid therapy, lack of
weight-bearing exercise, and diet.
Metabolic bone disease is common among patients with chronic liver disease.
Osteoporosis accounts for the majority of cases whereas osteomalacia is rare
in the absence of advanced liver disease and severe malabsorption. In this
review, we will consider hepatic osteodystrophy primarily as osteoporosis and
rarely osteomalacia. The reported prevalence of osteoporosis among patients
with chronic liver disease ranges from 20% to 100%, depending on patient
selection and diagnostic criteria. The pathogenesis is unclear and likely is
multifactorial. Regardless of the etiology of bone disease in these patients,
they have an increased incidence of bone pain and fractures, a major source
of morbidity preceding and following liver transplantation.
Pathogenesis
The etiology of hepatic osteodystrophy remains undefined. Histologically,
hepatic osteodystrophy is similar to postmenopausal and aging-related bone
loss in that trabecular (cancellous) bone is more rapidly and severely
affected than cortical bone. Potential inciting factors that either directly
or indirectly alter bone mass include insulin growth factor-1 (IGF-1)
deficiency, hyperbilirubinemia, hypogonadism (estrogen and testosterone
deficiency), alcoholism, excess tissue iron deposition, subnormal vitamin D
levels, vitamin D receptor genotype, osteprotegerin deficiency, and
immunosuppressive therapy preceding and following liver transplantation.
Maintenance of skeletal integrity involves a sequential coupling of
osteoclast-induced bone resorption with osteoblast-mediated bone formation
and subsequent osteoid mineralization at remodeling sites termed basic
multicellular units. For bone loss to take place, a negative remodeling
balance must occur with the amount of bone resorbed exceeding the amount
formed. 7 Dynamic histomorphometry, employing double tetracycline labeling
followed by iliac crest bone biopsy, lends some insight into the mechanism of
low bone mass formation in chronic liver disease patients. Several studies
suggest that reduced bone formation in
patients with chronic liver disease is the primary abnormality ('low
turnover' osteoporosis), whereas others report reduced or normal formation
coupled with increased resorption ('high turnover' osteoporosis).
Low turnover osteoporosis is characterized by a reduced synthesis of collagen
matrix and a low rate of mineralization. Osteoblast dysfunction has been
implicated and may result from reduced trophic factors such as IGF-1 or the
presence of excess putative growth inhibitors, e.g., bilirubin. IGF-1 pro
duction by the liver and bone is stimulated by circulating growth
hormone and insulin. IGF-1, in turn, stimulates osteoblast proliferation and
differentiation. In a rat model of hepatic osteodystrophy, low-dose IGF-1
increased bone mass and bone density. 11 Patients with cirrhosis and
osteoporosis have been found to have significantly lower serum IGF-1 levels
than patients with cirrhosis without osteoporosis or 'normal' controls.
Nonetheless, the exact role of IGF-1 deficiency in patients with hepatic
osteodystrophy has not been established. Substances retained in plasma
resulting from cholestasis may also contribute to osteoblast dysfunction. In
vitro, unconjugated bilirubin (but not bile salts) from the plasma of
patients with jaundice caused by hepatocellular and cholestatic chronic liver
disease or ductal
malignancies inhibits human osteoblast proliferation. This suggests that
depressed osteoblast function may be related to jaundice, independent of
etiology.
Hypogonadism is an established risk factor for osteoporosis. Chronic liver
disease accelerates the development of hypogonadism due to both reduced
hypothalamic release of gonadotrophins and primary gonadal failure. A decline
in circulating estrogen may be a mediator of bone loss in women and men with
chronic liver disease. Primary biliary cirrhosis (PBC) patients with
premature menopause have lower bone mass than those with normal menopause
age. Men
with advanced chronic liver disease develop hypogonadism, and with cirrhosis,
a further reduction in serum testosterone occurs. Because testosterone is
metabolized to estrogen, this results in a relative decline in blood estrogen
levels. A histomorphometric study among men with alcohol-induced cirrhosis
revealed an impaired bone formation rate and increased osteoclast eroded
surfaces that correlated with reduced testosterone levels. Serum estradiol
levels were not assessed. Factors such as chronic alcohol ingestion and
excess pituitary iron deposition (genetic hemachromatosis) may also
contribute to the development of hypogonadism independent of the cirrhotic
process. Furthermore, chronic alcohol use and an increased iron burden have
been associated with impaired osteoblast activity in vitro and in vivo,
respectively.
In the case of high turnover osteoporosis, synthesis of matrix and its
mineralization are normal, but osteoblasts are unable to fill the numerous
resorption cavities. High turnover osteoporosis has been described among 20%
to 30% of patients with chronic cholestatic liver disease, PBC, and primary
sclerosing cholangitis. The observed increase in osteoclast activity remains
unexplained, but may be related to hypogonadism as described above, or
vitamin D deficiency. Subnormal serum concentrations of 25-hydroxyvitamin D
among patients with chronic cholestatic liver disease have also been
reported. This is not believed to result from
reduced hepatic hydroxylation, but may result from malabsorption, increased
urinary excretion, or reduced enterohepatic circulation of vitamin D.
However, many studies have confirmed the lack of a relationship between low
25-hydroxyvitamin D levels and the presence or severity of osteoporosis.
Moreover, recent clinical trials that evaluated treatment with vitamin D
and/or 25-hydroxyvitamin D have been largely unsuccessful in reversing or
halting the progression of
osteoporosis as assessed by histomorphometry, bone mineral density, and
fracture incidence.
Although vitamin D deficiency per se is likely not implicated in the
development of hepatic osteodystrophy, reduced tissue sensitivity to
circulating vitamin D due to altered vitamin D receptor genotypes may play a
role. In normal individuals and patients with postmenopausal osteoporosis,
vitamin D receptor allelic polymorphisms, designated B/b, A/a, and T/t
alleles on the basis of restriction enzyme sites, correlate with bone mineral
density in some populations. The physiologic effect of vitamin D receptor
allelic polymorphisms is unknown, but may be related to altered intestinal
calcium absorption or tissue-specific variations in response to
1,25-dihydroxyvitamin D. In general, the degree of osteopenia correlates with
the severity of liver disease. 30,31 However, several studies of patients with
PBC have reported subgroups of patients with osteopenia before the
development of advanced liver disease, suggestive of a potential genetic
predisposition to bone loss. In a cohort of patients with PBC, vitamin D
receptor genotype correlated with lumbar spine bone mineral density, with an
allele dose effect. Indeed, the risk of developing a vertebral fracture
increased 2- to 3-fold with the presence of a T allele in this one study.
Factors other than gonadal hormones, vitamin D, and vitamin D receptor
genotypes likely play a role in the development of high turnover bone disease
in patients with hepatic osteodystrophy. Osteoprotegerin (OPG), a member of
the tumor necrosis factor receptor superfamily, has recently been found to
regulate bone turnover. Produced by the liver, OPG inhibits osteoclast
differentiation in vitro and in vivo. In a transgenic mice model, increased
hepatic expression of OPG resulted in osteopetrosis, or increased bone
density. The role of OPG in hepatic osteodystrophy is speculative; a decline
in liver function may be associated with reduced production of OPG and
increased osteoclast-mediated bone resorption.
Corticosteroid therapy is the primary therapy for autoimmune hepatitis and
has been the mainstay of immunosuppression after liver transplantation.
Trabecular bone loss is most rapid during the first 12 months of
corticosteroid use and usually occurs with prednisone doses exceeding 7.5
mg/d. Corticosteroids enhance osteoclast activity via the production of
interleukin 1 and interleukin 6 while paradoxically suppressing osteoblast
function by decreasing differentiation, recruitment, and life span as well as
indirectly through reduced synthesis of type I collagen and reduced
production of IGF-1. In addition, corticosteroids alter
intestinal calcium absorption, increase urinary calcium excretion with
resultant secondary hyperparathyroidism, and precipitate hypogonadism. The
net result is clinically significant bone loss with an increase in fracture
risk by greater than 2-fold.
Because of the deleterious metabolic effects of prolonged high dose
corticosteroid use, alternative immunosuppressive medications in conjunction
with reduced dosages of corticosteroids are used in all patients immediately
after liver transplantation. After liver transplantation, bone loss typically
follows a biphasic course. Accelerated bone loss occurs with up to 24%
deterioration in lumbar spine bone mineral density (measured by quantitative
computed tomography) within the initial 3 to 6 months after transplantation.
Stabilization and improvement of bone mineral density occurs during the
ensuing 12 months and may continue for years. Indeed, reversal of bone loss
after liver transplantation correlates with good hepatic allograft function,
suggestive that hepatic osteodystrophy results from the physical and
metabolic changes associated with the progressive deterioration of hepatic
function. Early bone loss after liver transplantation is not only attributed
to corticosteroids, but also to immunosuppressive agents such as the
calcineurin inhibitors. In rats, cyclosporin and tacrolimus have been found
to stimulate bone turnover by increasing trabecular bone remodeling sites
resulting in an increase in bone resorption. In addition, in this rat model,
increased
interleukin 1 synthesis, and reduced gonadal function occurred in response to
cyclosporine use and contributed to bone loss. Because calcineurin
inhibitors are used in conjunction with corticosteroids, the independent
effects of these agents on bone metabolism in humans is difficult to
ascertain.
Osteoporosis is a histologic diagnosis; however, clinical recognition relies
on noninvasive imaging studies such as bone mineral density measurements and
radiography, which enable an assessment of bone mass and fracture risk. The
World Health Organization defines osteoporosis as a bone mineral density 2.5
standard deviations below the young normal mean (T score). Severe or
'established' osteoporosis refers to individuals who meet the World Health
Organization definition and have radiographic evidence of one or more
fractures.
Dual energy x-ray absorptiometry is the method most commonly used to measure
bone mass because it is accurate and can measure multiple skeletal sites. The
primary hindrance to the widespread and routine use of dual energy x-ray
absorptiometry among patients with chronic liver disease is cost (and
potential lack of insurance coverage for screening) coupled with limited
pharmacologic intervention data. A less expensive bone mass measurement
technique such as quantitative ultrasound may serve as a useful screening
tool to identify affected individuals. Cancellous bone sites, i.e., the axial
skeleton, are preferred sites of evaluation because of their more rapid
change over time and with therapeutic intervention data on treatment
efficacy. Skeletal radiographs are useful adjuncts to bone mineral density
measurements, as the risk of future vertebral fracture is predicted by the
presence of preexisting spinal fractures.
Studies using noninvasive measurements of bone mass in unselected individuals
report an osteoporosis prevalence rate of 29% to 43%. However, the vertebral
fracture threshold among patients with chronic liver disease has been found
to be significantly higher (124-128 g/cm3 by quantitative computed tomography
[QCT]) than the generally accepted threshold of 98 g/cm3 in postmenopausal
women.47 The prevalence of atraumatic spinal and peripheral fractures ranges
from 8% to 32%, with a higher frequency noted among patients with cirrhosis.
Furthermore, the presence of osteoporosis before liver transplantation is an
important determinant of fracture development after transplantation.
Fractures of the vertebrae, ribs, and long bones have been reported in 24% to
65% of patients in the early (3 to 6 months) postoperative period. Such
fractures occur primarily among patients with a preoperative bone mineral
density below the fracturing threshold.
Accordingly, patients with cirrhosis or those receiving long-term
corticosteroid therapy should be screened for metabolic bone disease with a
bone mineral density study. If the patient reports loss of height, a
thoracolumbar spine radiograph may be obtained. In addition, several
biochemical tests may be useful to ascertain calcium metabolism and gonadal
hormone status: serum calcium, phosphate, thyroid function tests, intact
parathyroid hormone, 25-hydroxyvitamin D, free testosterone (men), serum
estradiol, and luteinizing hormone (women). Major abnormalities in
parathyroid function or vitamin D metabolism warrant referral to an
endocrinologist or metabolic bone specialist. The majority of patients will
have abnormalities of bone mineral density alone; those who meet the World
Health Organization definition of osteopenia, osteoporosis, or 'established'
osteoporosis are candidates for pharmacologic therapy.
MANAGEMENT
Potentially reversible factors that may effect bone loss should be eliminated
whenever possible. These include tobacco and alcohol cessation, reduction of
caffeine ingestion, as well as loop diuretic (i.e., furosemide) and
corticosteroid dosages. Regular weight-bearing exercise is integral to the
maintenance of skeletal integrity by maintaining both muscle and bone mass.
Exercise in combination with adequate dietary intake of calcium has been
shown to be effective for delaying the progression of bone loss in
postmenopausal women 48 and may prevent bone loss in liver disease patients.
For those patients with advanced liver disease, physical therapy with a focus
on strengthening of the back muscles may be of benefit. After liver
transplantation, physical therapy to facilitate early mobility is
imperative.40 Patients with symptomatic vertebral fractures or bone pain
should receive analgesics, muscle relaxants, and a spinal brace (in the case
of vertebral fractures) to facilitate mobility.
Nutritional therapy
Varying degrees of calcium malabsorption may occur in patients with chronic
liver disease due to malnutrition, vitamin D deficiency, the use of
cholestyramine, and/or corticosteroids. Early calcium supplementation is
important because of its bone-protective effects. Furthermore, a study of
osteoporotic women with PBC revealed an independent positive effect of oral
calcium on bone mineral density.50 Age-specific guidelines for calcium
requirements have been put forth by the NIH: adults at risk for osteoporosis
should ingest 1,500 mg of elemental calcium per day. Calcium carbonate and
calcium citrate are generally well tolerated and absorbed. Calcium
supplementation is especially warranted in the posttransplantation setting
during which there is a period of increased bone resorption followed by rapid
formation.
In the United States, overt vitamin D deficiency with osteomalacia is rare;
nonetheless, derangements of calcium and vitamin D often accompany chronic
liver disease. However, early trials of vitamin D administration in
osteoporotic patients with cholestatic liver disease failed to delay the
progression of osteoporosis as assessed by bone mineral density and fracture
incidence. 2,3,21,52 In a subsequent small randomized, controlled trial of
vitamin D-deficient patients with alcohol-induced liver disease and
osteoporosis, treatment with vitamin D (ergocalciferol, 50,000 IU three times
weekly or 25-hydroxycholecalciferol, 20 to 50 mg
daily) significantly increased bone mineral density compared with the
controls. In addition, patients with PBC54 and viral-induced cirrhosis 55
obtained a similar beneficial effect with calcitriol (0.5 mg twice daily) on
bone mineral density. However, baseline histomorphometry was not performed to
exclude underlying osteomalacia. Thus, routine administration of
pharmacologic doses of vitamin D in patients with chronic liver disease is
controversial.
Initial studies suggested that pharmacologic doses of calcitriol may improve
calcium absorption and stabilize bone mineral density in patients receiving
corticosteroids. However, the routine use of calcitriol among patients
treated with long-term corticosteroids fell out of favor because of a
negligible impact on fracture incidence and the potential for associated
toxicities (hypercalciuria and hypercalcemia). In a large randomized,
controlled study, patients with
rheumatoid arthritis receiving calcium and vitamin D (500 IU, equivalent to
one multiple vitamin a day) as well as low-dose prednisone exhibited
increased bone mineral density by comparison with those receiving placebo. In
the absence of histomorphometry suggestive of osteomalacia, there is little
evidence to support the routine administration of vitamin D beyond the
recommended daily allowance contained in 1 to 2 standard multivitamins (400
to 800 IU).
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