Journal of Hepatology
Volume 34, Issue 2 , Pages 337-338, February 2001

Post-liver transplantation osteoporosis

Division of General Internal Medicine and Clinical Epidemiology, Endocrinology, and the Osteoporosis Program, Department of Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, 657 University Avenue, Toronto, Ontario, Canada M5G 2N2

Received 3 November 2000; accepted 7 November 2000.

See Articles, pages 292–298 and 299–305

Article Outline

 

Osteoporosis is becoming a major cause of morbidity in the post-liver transplantation population. It is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures [1]. Data from observational studies suggest that bone loss post-liver transplantation is greatest within the first 3–6 months post-transplantation, and can be as high as 48% within the first year [2], [3], [4], [5], [6]. The etiology is often multifactorial; both pre-existing diseases and post-transplantation factors contribute to the problem. Recognized pre-existing risk factors in this population include cholestatic liver disease, alcoholism, hypogonadism, and abnormal hepatic vitamin D metabolism. The use of high dose steroids and other immunosuppressants such as cyclosporin and tacrolimus (FK506), immobility, and poor nutrition contribute to the excessive bone loss post-transplantation. Low-trauma or atraumatic fractures most often occur within the first 6 months post-transplantation, and can affect 7–65% of the population [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. The most common sites affected are spine, ribs, wrist, hip and pelvis. As the long-term survival of liver transplantation patients increase, one important question is whether these undesirable effects of liver transplantation on bone can be avoided.

This issue of the Journal contains two original articles that address this question [16], [23]. Hay and colleagues from the Mayo Clinic performed a randomized controlled trial of daily subcutaneous calcitonin versus no therapy for 6 months for 63 patients with primary biliary cirrhosis (n=26) and primary sclerosing cholangitis (n=37) undergoing liver transplantation [16]. The groups were comparable at baseline. Bone mineral densities (BMDs) fell significantly at 4 months, and stabilized between 4 and 12 months in both groups. There were no significant differences in BMDs and fracture rates between the two groups during the study period. Thus, the authors conclude that 6 months of calcitonin therapy does not prevent accelerated bone loss or spontaneous fractures within the first year post-liver transplantation. These results are disappointing as calcitonin is now available in an inhaled form, and unlike oral bisphosphonates, can be easily administered without regard to time of day, meals or other medications. These results differ from those from studies in other populations, which showed that calcitonin prevented steroid-induced bone loss [17] and postmenopausal vertebral fractures [18]. One possible explanation may be because the treatment duration was not long enough; most calcitonin studies in non-transplantation populations have used at least one year of therapy [17], [19], [20]. Another may be because calcitonin does not have strong enough antiresorptive properties to stop the accelerated bone loss post-liver transplantation [21], [22].

Isoniemi and colleagues from Helsinki, Finland, report the results of their 2-year prospective study of transdermal hormone replacement therapy (HRT) in this issue of the Journal as well [23]. They found that transdermal HRT increased BMD and decreased bone turnover markers in 33 postmenopausal women who had stable liver grafts with a mean of 4.1 years post-transplantation. While these results are promising, this study is not a randomized and controlled trial, and improvements may represent the natural history of BMD and bone turnover markers following transplantation instead of the effects of HRT per se. Furthermore, the sample size is small and there is no fracture data. Future studies are needed to further corroborate these encouraging results.

There have been only a handful of intervention studies published to date in this area, and most are not randomized controlled trials. One small study of 13 osteopenic patients treated with intravenous pamidronate before and after liver transplantation suggests that intravenous pamidronate may reduce fractures [24]. Another non-randomized study of 238 patients treated with two different doses of calcitriol±calcium, and with or without sodium fluoride, found a lower incidence of atraumatic fractures in the treated patients than in the 246 controls [25]. An earlier study of 53 consecutive patients prophylactically treated with oral cyclical etidronate, calcium and 1 alpha-hydroxyvitamin D3 found increased bone loss and a 25% vertebral fracture rate post-transplantation despite treatment [26]. The only randomized controlled trial in this area, other than the one performed by Hay and colleagues [16], found a significant increase of vertebral BMD at 12 months in 40 osteoporotic liver transplantation patients treated with either intramuscular calcitonin or oral ethiodronate [27]. However, again, it is unclear whether this increase is part of the natural history of transplantation or because of treatment since they did not have a placebo control group. Whether data from other groups of transplantation patients can be applied to the liver transplantation population is controversial, as liver patients have different predisposing risk factors than other transplantation groups.

Both of the articles in this issue of the Journal again raise our awareness of the increasingly important issue of post-liver transplantation osteoporosis. They also point to the great need of having adequately powered randomized controlled trials to identify efficacious therapies for the prevention of bone loss and fragility fractures in these patients. Additional issues to be addressed include duration of therapy, side-effect profiles (as many of these patients are already on a number of other medications), ease of administration, and how these medications affect quality of life in these patients. As the number of liver transplantations and the long-term survival of these patients increase, prevention of osteoporosis and osteoporotic fractures in post-liver transplantation patients should be a major priority.

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PII: S0168-8278(00)00070-2

Journal of Hepatology
Volume 34, Issue 2 , Pages 337-338, February 2001

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