DIAGNOSTIC AND THERAPEUTIC ASPECTS OF OSTEOPENIA AND OSTEOPOROSIS IN CHRONIC LIVER DISEASE
Diagnosis of osteopenia and osteoporosis
The main objective for assessing and treating HO is to prevent bone fractures. BMD is measured using dual energy X-ray bone absorptiometry performed on the lumbar vertebrae and femoral neck. The results of the measurement are classified on a scale by the World Health Organization, the t-score being the basic parameter for diagnosis. Osteoporosis is therefore defined as a BMD of less than 2.5 standard deviation compared to the normal average score for young adults (t-score of less than -2.5). Similarly, osteopenia is defined as having a t-score of between -1 and -2.5. Prospective studies show how the risk of fractures increases progressively in proportion to the decrease in BMD, with between a two-fold and three-fold increase per standard deviation decrease therein.
Assessment of all patients with chronic liver disease and suspected osteoporosis should include a hemogram and basic biochemistry, including liver function, phosphocalcium metabolism and gonadal and thyroid profile. A simple X-ray of the dorsal and lumbar vertebrae is indicated if there is a clinical suspicion of spinal fracture as this is an indication for treatment, irrespective of bone density.
During the bone remodeling process, enzymes and non-enzymatic peptides reach the bloodstream and/or are eliminated through urine. Their concentration in blood and urine is related to the total bone turnover rate. These products, or bone turnover markers (BTM), are divided into two groups: resorption markers and formation markers. The main osteosynthesis markers are procollagen type1carboxyterminal propeptide and procollagen type1aminoterminal propeptide, osteocalcin and alkaline phosphatase bone isoenzyme. Noteworthy among the resorption markers are the urinary excretion of deoxypyridinoline, pyridinoline, type 1 collagen amino-terminal telopeptide and hydroxyprolinuria, the latter being less specific. These markers are usually expressed in relationship to the urinary excretion of creatinine.
BTM are higher in patients with osteoporosis and there is an inverse relationship between their levels and BMD. Until now, there has been no particular consensus regarding the most appropriate strategy for their use in clinical practice, although it is thought that they could be useful for monitoring bone mass loss in response to treatment for osteoporosis and for predicting fracture risk. However, this extreme is yet to be verified, because there have been only a few studies with patients suffering from chronic liver disease carried out[52,53]. It would seem that BTM levels are influenced by the extent of hepatic fibrosis and by the intrahepatic metabolism of collagen in these individuals which could make it difficult to interpret the results obtained.
Treatment of osteoporosis in chronic liver disease
There are very few randomized-controlled intervention studies on the prevention of osteoporosis and fractures in chronic liver disease. Most of available data relate to studies performed on patients with PBC[6-8] and do not evaluate the effective reduction in fracture rates.
General non-pharmacological measures and specific antiosteoporotic drugs are available to treat HO.
General measures: These include lifestyle and nutritional measures aimed at correcting the reversible risk factors, such as alcohol consumption, smoking and making lifestyle changes by introducing regular moderate physical exercise.
Extensive studies have provided no evidence on the effect of calcium and vitamin D in preventing OP and fractures in these patients. Research has been performed on small groups yielding inconsistent BMD results[16,32,51]. However, it seems reasonable to recommend supplements by taking a daily dose of 800 UI of vitamin D3 and 1 g of calcium[9,54].
Specific drugs in the treatment of HO: Bisphosphonates are powerful anti-resorptive drugs that selectively inhibit osteoclast activity. These agents have been shown to reduce the risk of vertebral and non-vertebral fractures and increase BMD in postmenopausal women with osteoporosis who do not have liver disease. They have also been effective in preventing steroid-induced osteoporosis in patients with PBC. However, there are no long-term controlled studies developed to evaluate the efficiency of bisphosphonates in fracture-prevention in individuals with chronic liver disease. A study with 80 postmenopausal women with osteoporosis and chronic liver disease secondary to hepatitis virus B and C suggests that a cyclic etidronate treatment could be effective to reduce the incidence of bone fracture.
Alendronate improves BMD of patients with PBC[56,57], although it should be used with caution because of potential esophageal side effects. Risedronate seems to have a less toxic effect on the esophageal mucosa, which could be useful for treating patients with esophageal varices.
Consequently, bisphosphonates are the main pharmacological agents used in the treatment of HO nowadays, despite the fact that limited data on bisphosphonates-therapy in chronic liver disease are available[38,58,54].
Raloxifene is a selective estrogen receptor modulator. It has positive effects on the lumbar bone mass and femoral neck and reduces vertebral fracture risk in postmenopausal osteoporosis. In a small study of patients with PBC, raloxifene led to significant improvement in lumbar BMD after 1 year of treatment, while no improvement was observed in the femoral neck. Evaluation by a bone disease specialist is recommended before using raloxifene in individuals with hepatic disease.
Parathyroid hormone (PTH) is a bone-forming drug that is administered subcutaneously in dosages of 20 to 40 μg per day, achieving an increase in BMD and a decrease in vertebral fracture risk in postmenopausal osteoporosis. Few data are published on its usefulness in osteoporosis secondary to chronic liver disease. A study in rats with induced biliary cirrhosis showed that intermittent administration of human PTH increases BMD and could be effective to prevent loss of bone mass.
Treatment of hypogonadism in patients with chronic liver disease and HO remains controversial. Hormone replacement with testosterone in hypogonadic males without chronic liver disease was efficient and increased BMD. Hormone replacement therapy (HRT) with estrogen and progesterone was proposed as a safe treatment for women with chronic hepatopathy, administered either orally or transdermally and sequentially or continuously[62,63]. Following the publication of the HERS II and WHI studies questioning the safety of HRT, its use is currently not recommended. The increased risk of hepatocellular carcinoma related to this treatment should be taken into account by weighing up its benefits and risks and it should be better administered transdermally[9,37,59].
Orthotopic liver transplantation and bone metabolism: A high prevalence of low BMD among patients with chronic liver disease just before liver transplantation has been observed. Estimated rates range from 26% to 34% and from 11.5% to 14% for osteopenia and osteoporosis, respectively[66,67].
Immediately after orthotopic liver transplantation (OLT), there is a loss of BMD and fracture risk increases. However, in the long term, osteopenia improves in transplant patients, as shown by a prospective study of patients with PBC and PSC who underwent OLT. Thus, liver transplantation is an efficient long-term treatment for osteoporosis in chronic cholestatic liver disease. Biphosphonates have also shown to be useful to avoid bone loss in transplant patients[69,70] but there is no evidence to consider one single agent among this group of drugs as first line therapy.