Journal of Hepatology
Volume 38, Issue 6 , Pages 856-865, June 2003

Osteoporosis in liver diseases and after liver transplantation

  • J.Eileen Hay

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    • Corresponding Author InformationTel.: +1-507-266-6772; fax: +1-507-266-1856

Mayo Clinic, 200 First street SW, Rochester, MN 55905, USA

Article Outline

 

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1. Introduction 

Osteoporosis is a common complication of chronic liver disease from cholestatic disorders to autoimmune, alcoholic and posthepatitic cirrhosis. Its aetiology is poorly understood and may vary in different liver diseases. Most symptomatic bone diseases in patients with liver disease are revealed only after liver transplantation (OLT) when early rapid bone loss leads to a high rate of fracturing in the first postoperative year. Reduced bone mass before OLT is the main risk factor for posttransplant fracturing and, therefore, its understanding and management are of prime importance. Optimal management of posttransplant osteopenia requires consideration of pre- and posttransplant factors.

By WHO criteria, osteoporosis is defined as bone of reduced density to less than 2.5 standard deviations below normal adult peak bone mass, adjusted for male or female sex, i.e. T-score of less than −2.5. Implicit in this definition is that the bone, albeit of small volume, is normally mineralised (no osteomalacia) and has no other pathological changes. Reduced bone density of T-score of −1.0 to −2.5 is called osteopenia. Osteopenia is also used as a collective term for both osteopenia and osteoporosis.

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2. Aetiology of osteopenia before and after liver transplantation 

Bone undergoes continuous remodelling by a sequence of events whereby old bone undergoes resorption and is then replaced by new bone formation which must be mineralised by adequate calcium ([1], #103, [2], #102). Bone mass is maintained by a balance between resorption and formation, a process regulated by many hormones and growth factors (Fig. 1) ([2], #102, [3], #342). The major influences on bone metabolism are genetic, but also essential are mechanical stress (exercise and muscle activity), good nutrition, adequate calcium and vitamin D and a normal hormonal environment. The patient with chronic liver disease has many potential causes for thin bones (Table 1) but the importance of different aetiologic factors in different liver diseases is poorly defined.

Table 1. Potential causes of bone loss in liver diseases and after transplantation
Genetic factors
Female sex
Small body frame
?Vitamin D receptor phenotype

Abnormalities of calcium and vitamin D


Poor nutrition

Poor oral intake of protein/calories
Low body mass index

Lack of mechanical stress to bone

Immobility
Poor muscle mass

Hormonal abnormalities in males and females

Hypothalamic hypogonadism
Primary gonadal failure
Postmenopausal

Lifestyle effects

Alcoholism
Smoking

Drugs

Corticosteroids
Other immunosuppressive agents

Liver-related factors

Chronic cholestasis
Iron overload
?Effects of cirrhosis, e.g. IGF-1, osteoprotegerin

2.1. Abnormalities of calcium and vitamin D metabolism 

The potential for osteomalacia or rickets due to deficiencies of vitamin D and calcium exists in any jaundiced patient with intraluminal deficiency of bile salts and fat malabsorption, particularly in children with severe chronic cholestasis. Many abnormalities of calcium and vitamin D are indeed seen in the osteopenia associated with chronic cholestatic liver diseases – reduced absorption of both calcium and vitamin D and low serum levels of 25-hydroxyvitamin D ([4], #82, [5], #88, [6], #77). However, 1,25-dihydroxyvitamin D is often normal ([6], #77), 25-hydroxylation of vitamin D by the liver is usually preserved ([7], #83) and no correlation has ever been identified between osteopenia and low levels of vitamin D or calcium or parathyroid dysfunction ([8], #19, [9], #5). Histomorphometric studies have shown no evidence of osteomalacia ([10], #399). Even more compelling against a pathogenic role for vitamin D in cholestatic osteopenia, are two trials ([11], #74, [12], #75) in which vitamin D therapy did not prevent ongoing bone loss in primary biliary cirrhosis (PBC) despite normalising serum vitamin D levels. Similarly, children with chronic cholestasis generally show no correlation between osteopenia and serum levels of vitamin D ([13], #35) or between osteopenia and calcium malabsorption ([14], #46).

In alcoholic cirrhosis, hemochromatosis and autoimmune hepatitis, osteoporosis and low vitamin D levels are both common but no consistent correlation of osteopenia and indices of calcium or vitamin D metabolism has been found and most histomorphometric studies fail to show osteomalacia ([15], #385, [16], #386, [17], #59, [18], #72, [19], #332). However, in patients with posthepatitic cirrhosis due to hepatitis B or C, bone mineral density (BMD) has correlated with vitamin D levels ([20], #320, [21], #319).

2.2. Body mass index, other nutritional factors and alcohol ingestion 

Osteopenia in PBC has been shown to correlate with low body mass index (BMI) suggesting the importance of nutrition and/or muscle mass to normal bone density ([9], #5, [22], #317). Osteocalcin, a bone matrix protein synthesised by osteoblasts, is vitamin K-dependent but studies in PBC patients have shown no aetiologic link between osteopenia and vitamin K deficiency. Vitamin K therapy prevented bone loss in cirrhotic females with viral hepatitis ([23], #353) but the mechanism of this beneficial effect is unknown. Although suggested in children with cholestatic disease ([24], #55), no correlation of magnesium deficiency and osteopenia has been seen in adults. Skeletal copper content may be increased in Wilson disease with multiple skeletal complications including osteoporosis and osteomalacia ([25]). Chronic alcohol ingestion, even with normal hepatic and gonadal function, may be detrimental to bone metabolism, inducing osteoporosis, fracturing and low bone turnover ([26], #60, [27], #65, [28], #52), by a direct effect of alcohol on osteoblast function ([29], #343). Reduced intestinal calcium absorption occurs in chronic alcoholics but no other consistent abnormality of calcium homeostasis has been identified ([26], #60, [27], #65, [28], #52, [29], #343). Fracture risk increases with heavy drinking ([28], #52).

2.3. Hypogonadism 

Hormonal abnormalities and hypogonadism are common in males and females with chronic liver disease due to reduced gonadotrophin release from the hypothalamus and primary gonadal dysfunction. Hypogonadism is a risk factor for ‘high-turnover’ osteoporosis ([30], #379) but, although it certainly contributes to osteopenia in some patients, it is not the only factor for bone loss in patients with liver disease. Low serum testosterone levels are common in males with alcoholic cirrhosis but correlation with osteopenia in uncertain ([16], #386, [17], #59). In males with posthepatitic cirrhosis due to hepatitis B or C, serum testosterone and oestrogen levels were within the normal range but with worsening cirrhosis, testosterone decreased and oestrogen increased ([31], #53). Osteopenia in hemochromatosis is associated with low serum testosterone levels; increased iron overload may also play a role here, as bone formation markers are greater in those undergoing venesection ([32], #369, [33], #396). Amenorrhoeic females with cirrhosis and both cirrhotic and non-cirrhotic alcoholic liver disease, commonly have decreased hypothalamic function with low levels of luteinising and follicle-stimulating hormones (LH and FSH); serum levels of sex hormone-binding globulin and testosterone are normal with low oestradiol ([34], #381). Despite the frequency of hormonal abnormalities in advanced liver disease, no correlation between osteopenia and menopausal status has been established in the large studies of PBC patients ([9], #5, [35], #339).

2.4. Corticosteroids and other drugs 

Corticosteroids have many effects on bone ([36], #27), all of which cause bone loss – increased resorption, decreased formation and calcium malabsorption. This seems a likely aetiologic factor in the osteopenia of autoimmune hepatitis ([37], #33) though some studies have shown no or weak correlation with steroid dose ([38], #69, [39], #56); advanced liver disease with cirrhosis seems to be at least as important a determinant for osteopenia in these patients. Decreased bone formation is seen histomorphometrically in the osteoporosis of corticosteroid-treated autoimmune hepatitis ([40], #392) but the effects of steroids and liver disease cannot be separated. A small randomised trial of prednisolone therapy in 36 patients with PBC suggested increased bone loss in some treated patients ([41], #40). Combination therapy of ribavirin and interferon for hepatitis C has recently been implicated in bone loss ([42], #28) but these data need confirmation before any firm conclusions can be reached.

2.5. Chronic cholestasis 

Many studies have shown that osteopenia and fracturing are most severe in chronic cholestatic disease, particularly in advanced disease ([43], #346, [44], #355). In 646 consecutive patients undergoing OLT ([45], #356), the pretransplant T-score of the lumbar spine in PBC and primary sclerosing cholangitis (PSC) was significantly lower than in chronic active hepatitis (CAH) or alcoholic cirrhosis (Table 2). Females with PBC, only 30% of whom were cirrhotic, had lower bone density than an older group of patients with posthepatitic cirrhosis ([44], #355). The studies failing to show increased osteopenia in PBC generally have patients with earlier disease ([22], #317, [46], #44) or small numbers ([47], #43).

Table 2. Pretransplant bone density of the lumbar spine in patients with advanced cholestatic, posthepatitic and alcoholic cirrhosis [43]
Liver disease# PatientsT-score of lumbar spine (mean)
Primary biliary cirrhosis129−2.22
Primary sclerosing cholangitis160−1.93
Chronic active hepatitis199−1.23
Alcoholic cirrhosis59−0.86

In addition, increasing osteopenia is seen as PBC and PSC advance in severity with progressive jaundice ([9], #5, [13], #35, [35], #339, [48], #47, [49], #70). An inverse relationship between BMD of the lumbar spine and serum bilirubin was seen in 210 ambulatory PBC patients ([48], #47). The severity of osteopenia in 176 PBC patients was most severe in patients with stages 3 or 4 disease and the rate of bone loss correlated with bilirubin; osteopenia here correlated with patient age and BMI and males had as much osteopenia as their female counterparts ([9], #5). Similarly, 142 women with PBC showed correlation between osteoporosis and disease severity, as assessed by bilirubin and histologic stage, but not menopausal status ([35], #339). Clearly, the above studies show that cholestatic osteopenia is not simply an age-related or menopausal phenomenon and that the severity of osteopenia increases with advancing liver disease and jaundice.

The connection between cholestasis and osteopenia is unexplained. Histomorphometric studies have generally shown low bone formation ([10], #399, [50], #62, [51], #73, [52], #32) but some also show evidence of increasing bone turnover ([10], #399, [53], #341, [54], #305). Unfortunately, no correlation has ever been found between any histomorphometric abnormality and bilirubin, hepatic synthetic function or indices of calcium and vitamin D. Osteoblast proliferation was inhibited by unconjugated bilirubin in vitro and by the serum of jaundiced patients, suggesting that bilirubin may have a direct effect on bone metabolism ([55], #336).

2.6. Cirrhosis 

A correlation of osteoporosis with the severity of chronic liver disease itself, independent of other identified risk factors, has been seen, not only in cholestatic disease as above, but also in alcoholic cirrhosis, CAH, hemochromatosis and posthepatitic cirrhosis ([16], #386, [54], #305, [19], #332, [56], #316). Low levels of insulin-like growth factor (IGF-1), which is trophic for bone and stimulates osteoblast proliferation, have been described in patients with cirrhosis and osteoporosis ([56], #316, [57], #360), children with cholestatic disease ([14], #46) and in experimental animal models of osteopenia ([58], #373); low serum levels of growth hormone-binding protein and elevated levels of growth hormone have also been described ([57], #360). Low levels of osteoprotegerin (which regulates osteoclast activity) in liver disease has been postulated as a potential cause for increased bone resorption ([59], #372). Biochemical markers of bone resorption and formation, as well as histomorphometric studies, have shown no uniform mechanism of bone loss.

2.7. Genetic factors: vitamin D receptor genotype 

About 75% of the variance in bone density is genetically determined but the genes contributing to the regulation of bone mass are largely unknown. The vitamin D receptor (VDR) gene and its three common polymorphisms have been most extensively investigated with variable results. At the present time, the role of the VDR gene in regulating peak bone mass, bone turnover and response to calcium is not understood and VDR polymorphisms are of no predictive clinical value ([60], #376, [61], #358, [62], #371). There are two studies in liver patients: in osteoporotic PBC patients, the VDR genotype correlated with bone mass and the risk of vertebral fracture ([63], #9) but in viral and alcoholic cirrhosis, no relationship was found ([64], #20, [65], #330).

2.8. Posttransplant bone loss 

Symptomatic osteoporosis with fracturing after OLT represents the overlap of two conditions: preexisting osteopenia at OLT and rapid posttransplant bone loss ([66], #42). Posttransplant bone loss occurs in recipients of all solid organ transplants ([67], #34, [68], #37, [69], #45, [70], #24, [71], #41, [72], #13, [73], #15, [74], #314) and it is likely to be due to factors integral to the perioperative or posttransplant course. Its pathogenesis is poorly understood with no correlation seen with liver function, indices of calcium or vitamin D metabolism or osteocalcin levels. Early after OLT, corticosteroids undoubtedly have a major influence on the skeleton, with trabecular bone being most affected and the greatest bone loss coinciding temporally with the highest steroid dose. But bone loss varies greatly in individual patients on identical steroid regimens and no correlation is seen between bone loss and high-dose steroids for rejection. Hopefully, the contribution of steroids will be defined by the current use of steroid-free immunosuppressive regimens in some centres.

Other immunosuppressive medications also have potential to affect bone metabolism. Both cyclosporine and tacrolimus cause high-turnover osteopenia in animal studies but these results are difficult to extrapolate to humans ([75], #167, [76], #172, [77], #168, [78], #175, [79], #50, [80], #30) and their effects on bone loss in liver recipients remain undefined; the highest bone loss temporally coincides with the highest levels of these drugs early after OLT but no correlation has been found between bone loss and cyclosporine dose or blood levels. Increased osteocalcin levels were seen in liver recipients ([81], #390) and in PBC patients ([82], #16) treated with cyclosporine suggesting increased bone formation. Small studies comparing liver recipients treated with cyclosporine and tacrolimus have shown conflicting results ([83], #400, [84], #338). There are no human data on the skeletal effects of azathioprine, rapamycin, mycophenolate mofetil or the newer immunosuppressive agents. No other drug has consistently been implicated in bone loss in liver transplant recipients.

Hormonal status may be important and often improves by 4–6 months after OLT when bone density starts to improve. No studies have looked at the effect of immobility in early postOLT bone loss. VDR gene polymorphism may influence bone loss after OLT ([64], #20) but conclusive studies will need larger numbers of patients.

Histomorphometric studies with paired biopsies before and 3–4 months after OLT have tried to elucidate the underlying mechanism of bone loss and recovery ([85], #301, [86], #344, [87], #388). By 3 months after OLT, bone formation has increased from low pretransplant levels while resorption indices are unchanged. This suggests that the cellular events leading to rapid bone loss had already occurred by 3–4 months after OLT and that recovery is underway. The later recovery of bone mass, seen at least in osteopenic, cholestatic patients, is presumably secondary to the improved metabolic milieu but what actual factors contribute to this are unknown.

Fracturing after OLT depends, not on bone loss, but on actual bone density. Almost all liver recipients lose bone mass in the first 3 months, but it is those with preexisting osteopenia who lose enough bone to fall below the fracture threshold – the main determinant of fracture risk. The rapidity of early bone loss after OLT may affect bone strength for years and contribute to ongoing fractures even when BMD is improving ([88], #389).

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3. Clinical features of osteoporosis in liver disease and after OLT 

3.1. Osteoporosis in chronic liver disease 

The overall incidence of osteoporosis in PBC is 20–30% ([9], #5, [35], #339, [88], #389) but this increases to 40% in patients with end-stage disease ([86], #344). Fractures occur in about 8% patients, increasing to 21% in end-stage patients, most fractures occurring in the spine or ribs. The risk of osteoporosis in PBC has been shown to correlate with age, disease stage, BMI and history of fractures, but not sex or menopausal status ([86], #344, [9], #5, [34], #381). Seventy two percent of patients with stages 3 or 4 PBC, who were over 57 years, with a BMI <24, had osteoporosis compared to none with stages 1 or 2 disease, younger than 57 years with a BMI >24, with a gradation of risk between these two extremes ([9], #5). Generally, patients with PSC have less symptoms from osteopenia than patients with PBC since they are predominantly males and younger but in relation to expected bone density for the age and sex, they have just as much osteopenia as patients with PBC. Again, as in PBC, bone disease worsens with disease progression and 32% patients with advanced PSC have osteoporosis and 16% fractures before OLT ([9], #5, [35], #339, [88], #389). Osteoporosis is prevalent in children with biliary atresia and Alagille's syndrome and worsens with disease severity and progression ([13], #35, [14], #46, [24], #55).

Significant osteoporosis is reported in autoimmune hepatitis, hemochromatosis and alcoholic cirrhosis ([16], #386, [32], #369, [39], #56). Eighteen percent of 66 abstinent alcoholics with advanced cirrhosis had osteoporosis ([90], #308). Most studies in posthepatitic cirrhosis due to viral hepatitis C have shown significant osteopenia ([88], #389, [19], #332, [20], #320, [90], #308) with osteoporosis in 28% of pretransplant patients with hepatitis C and no history of alcohol abuse. On the other hand, in a large Japanese study of hepatitis C, only women over 60 years of age had significant osteopenia compared to the normal population ([91], #359).

3.2. Bone disease after liver transplantation 

Pretransplant osteopenia is often asymptomatic and overshadowed by the more urgent complications of end-stage liver disease. However, most liver recipients lose bone rapidly in the first 3–4 months after OLT. The amount of bone loss varies widely from 1.4 to 24% in reported series ([43], #346, [56], #316, [92], #309, [93], #393), with a mean bone loss of 4.6% in the largest series of 646 patients ([45], #356). Patients, who are already osteopenic before OLT, are the ones who will fall to the level of osteopenia necessary for fracturing. No preoperative or postoperative parameters, either of bone metabolism or hepatic function, can predict the postoperative bone loss of an individual patient.

Fortunately, bone density reaches a nadir around 3–6 months after OLT; bone loss then stops in most patients, and especially in those cholestatic patients with severe osteopenia, recovery of bone mass will occur with normal activity and normal allograft function, back towards a bone density more normal for age and sex ([43], #346, [45], #356, [94], #325). Recovery of bone mass is less in patients with abnormal allograft function ([43], #346, [45], #356, [94], #325).

As bone density is at its lowest in the first year after OLT, the incidence of fracturing is highest with fractures in 20–30% patients during this first year ([43], #346, [95], #92, [96], #94) and most studies showing a rapid decline in fracturing with years out from OLT. In 292 liver recipients transplanted for cholestatic disease ([88], #389), 43% of PBC patients and 30% with PSC sustained a fracture in the first postoperative year; although the incidence of fracturing fell dramatically thereafter, a small ongoing cumulative incidence of fracturing was seen and by 8 years, 64% of patients had sustained a fracture. This small, ongoing incidence of fractures has been confirmed in other studies ([95], #92) and might be explained by a more longstanding effect on the mechanical strength of the bone induced by the rapid posttransplant loss. The main pretransplant risk factor for fracturing in cholestatic and other patients is the presence of pretransplant fractures ([88], #389, [95], #92, [96], #94); pretransplant osteopenia, female sex and low serum albumin ([88], #389) and reOLT ([43], #346) are also predictive for fracturing. Fractures typically occur in areas of trabecular bone, predominantly the spine and ribs, with a very small incidence of pelvic and long bone fractures ([43], #346).

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4. Management of osteoporosis before and after OLT 

The management of osteoporosis in patients with chronic liver disease involves diagnosis, correction of any risk factors, supportive care to maximise bone health and consideration of specific therapies. Patients with chronic cholestatic disease have been the most extensively investigated but the results may be applicable to the non-cholestatic population. Posttransplant management is an extension of pretransplant care.

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4.1. Diagnosis by BMD measurement 

The diagnosis of osteopenia must be considered in any patient with advanced liver disease and certainly in all liver transplant candidates. All cholestatic patients, male or female, are at risk of developing osteopenia – their risk dependent on age, stage and duration of the cholestatic liver disease, BMI and other risk factors. Liver-specific risk factors for other liver diseases are less well characterised, although long-term steroid therapy in autoimmune disease is an obvious example.

Until fractures occur, no clinical or biochemical marker of calcium or vitamin D metabolism, cholestasis or hepatic synthetic function will identify the patient with osteopenia and, therefore, BMD must be measured. Fortunately, there are sensitive, highly specific, non-invasive techniques, which measure BMD with excellent precision; the most commonly used method is dual-energy X-ray absorptiometry (DEXA). BMD measurements of lumbar spine or femur are recorded as an absolute value and also as a T-score, a sex-adjusted value compared to peak bone mass of the normal population. A baseline BMD of the lumbar spine should be done in all patients with advanced liver disease, in patients with earlier liver disease with additional risk factors, in all cholestatics at diagnosis and in all potential liver transplant candidates; clinical progression can easily be followed by serial measurements, depending on baseline level and other risk factors. Patients with osteoporosis should undergo radiographs of thoracic and lumbar spine to assess for compression fractures. Histomorphometric assessment of a bone biopsy is unhelpful clinically for management of the individual patient.

4.2. Correction of any risk factors 

All reversible causes of bone loss must be aggressively sought and treated. Indices of calcium and vitamin D metabolism, including parathyroid hormone level, are measured and any obvious deficiency treated. Assessment is made of gonadal status and drug therapy, with any osteopenia-producing drugs reduced to minimum (steroids, thyroid replacement). Lifestyle changes to promote bone health should be recommended.

One risk factor for bone loss in the posttransplant period is assumed to be high-dose steroids but the magnitude of the effect of steroids has not been quantified; generally, steroid use is minimised as much as possible in the presence of osteoporosis. The immunosuppressive regimen, most advantageous to skeletal health, is yet to be defined.

4.3. Supportive measures for bone health 

In the absence of proven effective therapies for hepatic osteoporosis, supportive measures to reduce bone loss should be implemented before and after OLT (Table 3). Nutritional status is important with adequate protein and calories to maximise bone and muscle health. Regular exercise can increase the mineral content of bone especially if combined with adequate dietary calcium ([97], #91). Exercise must be ongoing and tailored to the individual to avoid further musculoskeletal complications and non-compliance. The optimal exercise programme to avoid or treat osteoporosis in patients with chronic liver disease or after OLT has not yet been determined. The minimum desirable level of activity is full mobility, a regular walking programme and exercises and instructions for the care and strengthening of the back. A full physical therapy programme may be necessary for implementation of activity in the debilitated patient before and/or after OLT.

Table 3. Supportive measures for bone health
Correction of any risk factors
Avoidance of deleterious lifestyle influences
Nutrition – adequate protein and calories
Regular weight-bearing exercise
Physical therapy if needed
Calcium supplementation, 1.5 g per day
Adequate vitamin D – therapy or RDA
Hormone replacement therapy

A high calcium diet is bone-protective in age-related bone loss ([98], #11) and in postmenopausal osteoporosis ([99], #12) especially when combined with exercise. In a small crossover study in PBC, calcium supplementation to both patients treated with calcitonin and to the controls resulted in increased bone mass in both groups ([89], #300). After OLT, osteopenic bone has the potential to recover, a process for which positive calcium balance is essential. The NIH age-specific guidelines for calcium supplementation is 1500 mg/d for all adults at risk of osteoporosis.

Vitamin D therapy has no efficacy in treating the osteopenia of PBC despite normalising blood levels of 25-hydroxyvitamin D ([11], #74, [12], #75) although in 18 alcoholic patients, it had some beneficial effect on bone density ([18], #72). It seems reasonable to use adequate oral supplementation with vitamin D to normalise blood levels, maximise calcium absorption and avoid any component of osteomalacia; this is especially important in children with severe cholestasis. Supplementation is usually satisfactorily given as 50,000IU of vitamin D2 given orally three times per week; some recent reports, in PBC and posthepatitic cirrhosis, advise the use of calcitriol, the active 1,25-dihydroxyvitamin D ([100], #349, [101], #26) but this has not been tested against regular vitamin D. The combination of calcium plus calcitriol (0.5 μg/day) was beneficial in liver recipients ([102], #310). Cholestyramine therapy reduces the intestinal absorption of fat-soluble vitamins, including vitamin D, and may contribute to calcium malabsorption. With normal serum levels of 25-hydroxyvitamin D, a standard multivitamin preparation with 400IU is given.

Oestrogen is antiresorptive for bone and hormone replacement therapy (HRT) is standard therapy for postmenopausal osteoporosis but has been avoided in patients with liver disease because of the potential hepatic side effects. However, in two small studies in postmenopausal patients with PBC, an increase in BMD of the lumbar spine was seen without any increasing cholestatic problems ([103], #335, [104], #391). Similarly, HRT was safe and effective in autoimmune hepatitis ([105], #368). Therefore, in the absence of a contraindication, HRT should be considered in postmenopausal patients with liver disease and osteopenia, especially if OLT is being considered. At the present time, there are no guidelines for the optimal therapy of premenopausal females with hypothalamic amenorrhoea or pretransplant males with low testosterone. Testosterone supplementation has been effective in hypogonadal men with hemochromatosis ([33], #396).

There are few data on the efficacy or safety of HRT in liver transplant recipients. The osteopenia of 30 postmenopausal liver transplant recipients improved with 2 years of transdermal oestrogen while on immunosuppression with cyclosporine and steroids, without any side effects ([106], #186). In the absence of large randomised trials, it seems reasonable to consider HRT in postmenopausal, osteopenic liver transplant recipients to avoid the addition of postmenopausal bone loss. Most liver transplant recipients are now managed in the long-term without steroid therapy; however, for the patient who requires ongoing steroid therapy, HRT may also help to protect against steroid-induced, and perhaps cyclosporine-induced bone loss ([107], #189).

4.4. Specific measures for osteoporosis 

4.4.1. Hormone therapy 

The use of HRT in postmenopausal women is recommended both before and after OLT. Before OLT, little is known about the use of hormone therapy in amenorrhoeic, premenopausal women or males with low testosterone. Gonadal function should normalise in these patients by 4–6 months after OLT; persisting hypogonadism after 6 months postOLT may warrant consideration of hormone therapy but there are no data regarding its effect on the bone mass of these patients.

4.4.2. Calcitonin 

Calcitonin is another agent, antiresorptive for bone, with efficacy in postmenopausal and steroid-induced osteopenia by the subcutaneous or intranasal route ([108], #187, [109], #215, [110], #367, [111], #10). A small prospective study of 25 osteopenic patients with PBC did not show any beneficial effect from 6 months of therapy, but patient numbers were small and the treatment period short ([89], #300). Osteopenic patients with PBC, treated with calcium, calcitriol and low-dose calcitonin had an improvement in BMD but the efficacy of calcitonin alone here could not be assessed ([112], #333). Calcitonin may be given for symptomatic relief of bone pain in patients with fracturing.

In a randomised trial of patients undergoing OLT for cholestatic disease, calcitonin therapy started in the first week after OLT was ineffective in preventing early rapid posttransplant bone loss and fractures in the first year ([113], #223). Osteoporotic liver transplant recipients with z scores <−2 were treated with calcitonin or cyclical etidronate, with an increase in BMD after 1 year ([114], #245), however, this was not a randomised study and it is not clear when in the posttransplant course, treatment was started.

4.4.3. Bisphosphonates 

These drugs are potent inhibitors of bone resorption by osteoclasts and their efficacy is seen in postmenopausal ([115], #365, [116], #364) and steroid-induced osteoporosis ([117], #397, [118], #14). Etidronate has now been superseded by the more potent intravenous pamidronate or oral alendronate and risedronate. Trials of these agents in patients with liver disease have been limited (Table 4). Patients with PBC were treated for 2 years with cyclical etidronate or fluoride and, although etidronate appeared beneficial, no significant change was seen with either therapy ([119], #238). In a small trial in PBC patients treated with low-dose steroids and azathioprine, bone loss was reduced by use of cyclical etidronate ([120], #361). Thirteen PBC patients per treatment group completed therapy with alendronate (10 mg/d) or cyclical etidronate with greater increase in BMD of the lumbar spine (5.8 vs. 1.9%) and femoral head (3.5 vs. 0.4%) in the alendronate group; no significant side effects were seen with either therapy ([121], #307). The ulcerative gastrointestinal side effects of the oral agents have limited their use in patients with portal hypertension and varices. Pamidronate, given by intravenous infusion every 3 months, is an alternative.

Table 4. Treatment trials in osteoporosis in liver diseases
Liver diseaseReferencesAgent# PatientsType of studyResults
PBC[122]Fluoride22Placebo-controlledNo fractures
PBC[87]Calcitonin25Crossover with placeboNo efficacy
PBC[124]UDCA88PlaceboNo efficacy
OLT recipients[112]Etidronate or calcitonin40No controls?Some efficacy
OLT recipients[120]Etidronate53No controlsNo prevention of bone loss
PBC[117]Etidronate23Compared to fluorideNo BMD change, less numbers
PBC[110]Calcitonin23No controls?Benefit from calcium+vitamin D
PBC[110]Etidronate12No controlsNo bone loss on steroids
At OLT[118]Pamidronate13Historic controlsNo postOLT fractures
OLT recipients[121]Fluoride49Not randomisedIncreased BMD but calcium/vitamin D also
At OLT[111]Calcitonin63Randomised trialNo efficacy
PBC[119]Alendronate26Compared to etidronateIncrease in BMD

Oral cyclical etidronate is of no proven efficacy in liver recipients ([122], #36) but encouraging results have been found with the more potent pamidronate. Because of a high incidence of posttransplant fractures in osteopenic patients, 13 liver transplant candidates with osteopenia were treated with intravenous pamidronate every 3 months before OLT and for 9 months after OLT with prevention of any posttransplant fractures ([123], #348). As yet, no therapeutic trials with sufficient patient numbers have tested the efficacy of the newer bisphosphonates in the treatment of hepatic or posttransplant osteoporosis.

4.4.4. Fluoride 

Sodium fluoride stimulates osteoblast proliferation and increases bone density but an excessive dose of fluoride results in increased bone fragility. In postmenopausal women, fluoride increased BMD without reducing fractures and, although lower dose fluoride is probably efficacious, fracturing is the necessary endpoint of trials with this agent. Patients with PBC were treated with fluoride (50 mg/d) or placebo for 2 years with improvement in BMD in treated group but no patients sustained new fractures to allow assessment of efficacy ([124], #21). Liver recipients, treated with 25 mg/d of sodium fluoride in combination with calcitriol and calcium, had beneficial results ([123], #348) but the effect of fluoride here is difficult to assess. Despite these encouraging, preliminary results, the benefit of fluoride in liver patients is unknown and fluoride is not Food and Drug Administration (FDA)-approved.

4.4.5. Miscellaneous agents 

Ursodeoxycholic acid (UDCA) can increase calcium absorption in PBC but its use for 3 years in 88 patients with PBC had no effect on BMD ([124], #21).

4.4.6. Liver transplantation 

The early months after OLT exacerbate any preexisting osteopenia in patients with chronic liver disease and fracturing becomes a major cause of morbidity in the first postOLT year. Despite this, severe osteopenia, at least in cholestatic liver disease, improves in the long-term after OLT and this must be considered the most proven efficacious therapy at this time for hepatic osteopenia. To maximise this benefit of OLT without the preceding morbidity is an ongoing challenge; its solution will demand a greater understanding of the aetiology of bone loss in liver disease and after OLT and the development of better drugs which will stimulate bone formation and will hopefully compliment the presently available antiresorptive agents.

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References 

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PII: S0168-8278(03)00143-0

doi:10.1016/S0168-8278(03)00143-0

Journal of Hepatology
Volume 38, Issue 6 , Pages 856-865, June 2003

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