Chronic liver disease and skeletal health (hepatic osteodystrophy)T Bandgar, V Shivane, A Lila, N Shah
Department of Endocrinology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.97170
Source of Support: None, Conflict of Interest: None
Metabolic bone disease is a common complication of chronic liver disease (CLD), ranging from cholestatic disorders to alcoholic, autoimmune and post-viral cirrhosis. 
Often known as hepatic osteodystrophy (HO), this is of two types: 1. osteoporosis that is similar to post-menopausal and aging-related bone loss; this type is more frequently seen and trabecular (cancellous) bone is more severely affected than cortical bone; 2. osteomalacia that is found in cases of advanced liver disease, in the presence of severe cholestasis (clinically manifested as jaundice) and malabsorption. In CLD, analyses have generally been performed not only in cirrhotics with a broad range of disease severity but also in pre-cirrhotic patients. The etiology of HO is poorly understood and is thought to vary according to the type, severity and progression of the liver disease, along with a multitude of other contributing factors, including the ethnicity of the population studied. It can result in spontaneous low-trauma fractures that significantly impact survival and quality of life, through pain, deformity and immobility. With orthotopic liver transplantation (OLT) steadily taking the center stage in the treatment of end-stage cirrhosis and offering long-term survival, bone disease has snowballed into one of the major determinants of survival and quality of life in this cohort.  Several cross-sectional and longitudinal studies have shown, despite considerable heterogeneity in case selection and methodology, that individuals with CLD have a pronounced loss of bone mineral density (BMD) (osteoporosis prevalence of 20-50%) and a moderately increased rate of osteoporotic fractures (5-20%).  Sachdev et al.  and George et al.  have reported low BMD in 64% and 68% of Asian Indian patients with CLD respectively.
The major controversy regarding the mechanism of osteoporosis in CLD is whether it is because of less bone formation or more bone resorption. In low-turnover osteoporosis (80%), bone remodeling unit (BMU) activity is severely affected (parenchymal liver disease), whereas in high-turnover osteoporosis (20%), BMU activity is increased (cholestatic liver diseases).  In our study of Asian Indian patients with non-cholestatic etiology of liver diseases, the mechanism of HO has been shown to be due to decreased bone formation with increased bone resorption. 
Loss of bone mass is quite a common finding in chronic hepatic dysfunction. Potential inciting factors that either directly or indirectly alter bone mass include insulin growth factor-I (IGF-I) deficiency, hyperbilirubinemia, hypogonadism (estrogen and testosterone deficiency), alcoholism, excess tissue iron deposition, subnormal vitamin D levels, vitamin D receptor genotype and osteoprotegerin (OPG) and receptor activator of nuclearfactor Kb ligand (RANKL) interactions. Furthermore, immunosupressants and antiviral agents such as interferon and ribavirin may affect bone metabolism.  Cholestatic disease per se does not differ significantly from non-cholestatic disorders in terms of osteoporosis and fracture risk. 
The source is the liver and osteoblast, which is important for the development and maintenance of bone mass. Earlier studies have shown that the severity of CLD from chronic hepatitis to cirrhosis is associated with a progressive increase of growth hormone resistance and with low IGF-I serum levels. 
Increased levels found in CLD patients results in decreased IGF-1 generation, and has an inhibitory effect on the osteoblast. However, Smith et al. concluded that hyperbilirubinemia is not a major contributing factor for low bone mass in patients with CLD. 
It is an established risk factor for osteoporosis, and CLD accelerates the development of hypogonadism due to altered hypothalmo-pituitary function with reduced release of gonadotrophins, and primary gonadal failure.
In CLD patients, a subnormal serum concentration of vitamin D is not a consequence of reduced hepatic hydroxylation, but is due to malabsorption, increased urinary excretion and reduced enterohepatic circulation of Vitamin D. Given the ubiquitous prevalence of Vitamin D deficiency in the Asian Indian population in all the age groups, this may prove to be an important contributory factor in this part of the subcontinent. Subsequent hepatic 25-hydroxylation of vitamin D3 has not been studied in humans but, in cirrhotic rats, this process is not impaired. , Reduced tissue sensitivity to circulating Vitamin D due to altered Vitamin D receptor genotypes may also play a role in the development of HO. Vitamin D receptor allelic polymorphisms, designated B/b, A/a and T/t alleles, correlate with BMD. The risk of developing a vertebral fracture increased two- to three-fold with the presence of a T/t allele. 
In CLD, deficiency of Vitamin K is also seen, especially in cholestatic liver disease. Vitamin K is required for the formation of osteocalcin and osteonectin. Supplementation of Vitamin K is associated with improvements in BMD. Furthermore, Vitamin K2 inhibits expression of ligand (RANKL), tartrate-resistant acid phosphatase (TRAP) activity, mononuclear cell formation and also induces osteoclast apoptosis in vitro.
OPG (tumor necrosis factor receptor super family) is produced by the liver and it inhibits osteoclast differentiation, whereas RANKL plays a role in the differentiation and activation of osteoclasts by binding to its high-affinity receptor (RANK) located on the surface of the osteoclasts. The role of OPG in hepatic osteodystrophy is not yet clear. Studies have shown that circulating OPG is increased and soluble RANKL is decreased, regardless of osteoporosis, contrary to the expectation in CLD.  Probably, there is a qualitative change in the OPG/RANKL system that contributes to the low bone mass in CLD patients.
Corticosteroid forms the therapeutic component for autoimmune hepatitis and for immunosuppression after liver transplantation. Prolonged steroid therapy results in clinically significant bone loss with an increase in fracture risk by greater than two-fold.  Steroids exert a direct effect on the bone cells by increasing the osteoclastic activity by increasing IL1 and IL6 and decreasing differentiation, recruitment and life span of osteoblast. Calcineurin inhibitors  are used in conjunction with corticosteroids; therefore, the independent effect of these agents on bone metabolism in humans is difficult to ascertain. Additional medications used in the treatment of advanced liver disease, such as diuretics, anticoagulants and chemotherapy, also have a deleterious effect on the bone.
Osteoporosis is frequently observed in the alcoholic patient. Ethanol decreases bone formation in a dose-dependent fashion, mainly through a direct toxic effect on osteoblast function.  It also alters, both directly and indirectly, bone mineral metabolism including PTH, Vitamin D, testosterone, IGF-1, cytokines (raised TNF and IL-6) and cortisol levels.
An increased iron burden has been associated with impaired osteoblast activity. Excess pituitary iron deposition (genetic hemachromatosis) may also contribute to the development of hypogonadism independent of the cirrhotic process. 
Contributing factors for low bone mass in our study on the Asian Indian population with non cholestatic liver cirrhosis were inadequate sunlight exposure, reduced physical activity, low lean body mass, Vitamin D deficiency and hypogonadism, along with IGF-1 deficiency and low estrogen in men.  The presence of most risk factors in low and normal BMD groups indicated that all Asian Indian patients with cirrhosis are vulnerable and, unless prevented, will develop the disease
Clinically, these patients present with bone pains, backache, loss of height, fragility fractures and kyphosis/scoliosis.
Various 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, bioavailable testosterone (men), serum estradiol and follicular stimulating hormone, luteinizing hormone. Other tests include X-ray, dual energy X-ray absorptiometry (DXA) scan, quantitative computerized tomography and biochemical markers of bone disease.
Chronic cholestasis, alcohol abuse, post-menopausal women with additional risk factors for osteoporosis, male hypogonadism, long-term corticosteroid therapy (more than 3 months), any patient with a fragility fracture, low body mass index and evaluation for transplantation.
Further monitoring with DXA
(1) Patients with normal BMD: 2-3 yearly; (2) high risk characters, viz. in cholestatic patients with more than one risk factor for osteoporosis, and in those recently initiating high-dose corticosteroid therapies: 1 yearly.
Biochemical markers of bone disease, viz. bone formation (procollagen propeptides of type 1 collagen, osteocalcin and bone isoenzyme of alkaline phosphatase), while bone resorption (urinary excretion of deoxypyridinoline, pyridinoline and Type 1 collagen cross-linked N-telopeptide) has not been studied in patients with CLD. Hence, it cannot be recommended.
The prevention of fragility fractures, and not the improvement of BMD, is the ultimate clinical goal for patients with osteoporosis. It is vital to optimize other factors that help reduce the risk of falls and fractures. The clinical approach is depicted in [Figure 1].
With the advent of OLT in the management of CLD, two stages of intervention for improving bone mass may be suggested: pre- and post-OLT.
Pre-orthotopic liver transplantation
Low bone turnover ,, is present before the procedure. It has been shown that low BMD and the presence of vertebral fractures before OLT are strong predictors of post-transplant fragility fractures.  Therefore, efforts to optimize and preserve lifetime bone mass should be initiated very early in all patients with progressive CLD, irrespective of whether transplantation is on the horizon or not, and continued through all the stages.
The following general measures are a must:
Bone loss and fracture rates after OLT are highest in the first 6-12 months. Spine BMD declined by 2-24% during the first year in earlier studies,  followed by an improvement of BMD 12 months post-transplantation. Fracture rates range from 24 to 65%, and the ribs and vertebrae are the most common sites.  Women with primary biliary cirrhosis and the most severe pre-existing bone disease appear to be at greatest risk.
After OLT, bone turnover is increased, but the cause of rapid bone loss immediately after OLT is not completely understood. Several factors, including post-operative immobility and high-dose glucocorticoid treatment, are likely to play a role.
Prevention and treatment
Both oral and iv bisphosphonates are effective in reducing post-OLT bone loss. A 12-month randomized study of 30 mg iv pamidronate every 3 months showed that pamidronate increased spinal BMD but did not prevent femoral neck bone loss.  A randomized trial of iv bandronate in OLT recipients prevented bone loss at 1 year. A randomized, double-blind trial of adults having liver transplantation showed that infusions of 4 mg zolendronic acid within 7 days of liver transplantation and again at 1, 3, 6 and 9 months after OLT  reduced bone loss by 3.8-4.7% at the LS, femoral neck and total hip compared with patients receiving saline infusions. At 12 months after transplantation, the differences only remained significant at the total hip. One study used historical controls to examine the effects of alendronate in addition to calcium and calcitriol 0.5 mcg daily after LT. Increases in spinal, femoral neck and total hip BMD at 12 months were higher than in historical controls. 
Management of low bone mass in children is similar to that in adults, where the role of prevention is most important with Vitamin D/calcium, physical activity, esp vibrating platform to stimulate muscle activity and, consequently, bone strength. In the management of children who have sustained osteoporotic fractures, the treatment for which currently there is the most evidence of benefit is bisphosphonates. ,
Older agents, viz. hormone replacement therapy, calcitonin and strontium ranelate have fallen out of favor in the management of osteoporosis either due to their side-effect profile or inefficacy.