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Bone Loss in Liver Disease
  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.
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.
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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