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Bone loss at the proximal femur and reduced lean mass following liver transplantation: a longitudinal study
APPLIED NUTRITIONAL INVESTIGATION
Nutrition Vol. 15, No. 9, 1999
Bone Loss at the Proximal Femur and Reduced Lean Mass Following Liver Transplantation: A Longitudinal Study JENNIFER B. KEOGH, MSC,* CON TSALAMANDRIS, MBBS,† RICHARD B. SEWELL, MD,‡ ROBERT M. JONES, FRACS,§ PETER W. ANGUS, MD,‡ IBOLYA B. NYULASI, MSC,* AND EGO SEEMAN, MD† From the Departments of *Nutrition and Dietetics, †Endocrinology, ‡Gastroenterology, and §Surgery, Austin and Repatriation Medical Centre, Melbourne, Australia ABSTRACT
The longevity of recipients of liver transplant may be compromised by spinal osteoporosis and vertebral fractures. However, femoral neck fractures are associated with a higher morbidity and mortality than spine fractures. As there is little information on bone loss at this clinically important site of fracture, the aim of this study was to determine whether accelerated bone loss occurs at the proximal femur following transplantation. Bone mineral density and body composition were measured at the femoral neck, lumbar spine and total body, using dual x-ray absorptiometry in 22 men and 19 women, age 46 ⫾ 1.4 y (mean ⫾ SEM) before and at a mean of 19 mo after surgery (range 3– 44). Results were expressed in absolute terms (g/cm2) and as a z score. Before transplantation, z scores for bone mineral density were reduced at the femoral neck (⫺0.47 ⫾ 0.21 SD), trochanter (⫺0.56 ⫾ 0.19 SD), Ward’s triangle (⫺0.35 ⫾ 0.14 SD), lumbar spine (⫺0.76 ⫾ 0.13 SD), and total body (⫺0.78 ⫾ 0.15 SD) (all P ⬍ 0.01 to ⬍ 0.001). Following transplantation, bone mineral density decreased by 8.0 ⫾ 1.7% at the femoral neck (P ⱕ 0.01) and by 2.0 ⫾ 1.2% at the lumbar spine (P ⱕ 0.05). Total weight increased by 12.2 ⫾ 2.3%, lean mass decreased by 5.7 ⫾ 1.4%, while fat mass increased from 24.1 ⫾ 2.0% to 35.1 ⫾ 1.8% (all P ⱕ 0.001). Patients with end-stage liver disease have reduced bone mineral density. Liver transplantation is associated with a rapid decrease in bone mineral density at the proximal femur, further increasing fracture risk and a reduction in lean (muscle) mass, which may also predispose to falls. Prophylactic therapy to prevent further bone loss should be considered in patients after liver transplantation. Nutrition 1999;15:661– 664. ©Elsevier Science Inc. 1999 Key words: bone mineral density, liver transplantation, femoral neck fractures, body composition
INTRODUCTION
The short- and long-term survival after liver transplantation is excellent and attention has now been directed at quality of life and the potential long-term complications following successful transplant surgery.1,2 One important long-term clinical problem is osteoporosis. Osteoporosis has been documented in patients with end-stage liver disease before transplantation and accelerated bone loss at the lumbar spine has been reported following transplantation, with spine fractures occurring in 17– 65% of patients in the first 12 mo after transplantation.2–10 This occurrence of bone loss at the spine early in disease is a consequence of the high proportion of trabecular bone in the vertebral body. Trabecular bone has a higher surface-to-volume ratio than cortical bone. This trabecular surface is in close proximity to the marrow in the vertebral body so that bone loss, a
surface phenomenon, occurs more rapidly at trabecular sites predisposing to the earlier emergence of bone fragility at this site.11 By contrast, the proximal femur is predominantly cortical and contains a less cellular marrow than the vertebral body.12 Both of these characteristics are likely to contribute to the slower rate of bone loss at this site seen during aging and following exposure to corticosteroids.13 The effects of liver transplantation on bone mineral density (BMD) at the proximal femur have not been well described. A high rate of bone loss at this site will predispose to hip fractures, with attendant high morbidity and mortality. The aim of this study was to document whether accelerated bone loss occurs at the proximal femur and whether muscle mass decreases following transplantation, since decreased muscle mass may predispose to falls and hip fracture. The results of this study draw attention to the increased risk of hip fracture in these patients.
Correspondence to: Jennifer B. Keogh, MSc, Nutrition Department, Alfred Hospital, P.O. Box 315, Prahran, Melbourne 3181, Australia.
Nutrition 15:661– 664, 1999 ©Elsevier Science Inc. 1999 Printed in the USA. All rights reserved.
0899-9007/99/$20.00 PII S0899-9007(99)00121-5
662
LIVER TRANSPLANTATION AND BONE LOSS AT THE FEMUR MATERIALS AND METHODS
TABLE I.
Patients BMD and body composition were measured as part of the liver transplantation assessment protocol of the Victorian Liver Transplant Unit and ongoing clinical management of transplant recipients. Data were available for 41 patients with end-stage liver disease who underwent liver transplantation between 1988 and 1994. There were 22 men and 19 women with a mean age of 46 ⫾ 1.4 y (range 25– 66). The etiology of liver disease included primary sclerosing cholangitis (PSC) (12), primary biliary cirrhosis (PBC) (6), chronic active hepatitis (5), alcoholic cirrhosis (5), autoimmune chronic active hepatitis (5), secondary malignancy (1), Wilson’s disease (2), cryptogenic cirrhosis (1), secondary biliary cirrhosis (1), acute hepatic necrosis (1), chronic BuddChiari syndrome (1), and hemachromatosis (1). Of the 19 women, 11 were postmenopausal at the time of transplant and a further 3 experienced menopause in the time between transplant and repeat DXA measurement. All patients were treated with cyclosporine, prednisolone, and azathioprine following transplantation. Prednisolone was commenced at 200 mg/d. The dose was reduced by day 5 to 20 mg/d for 3 mo, and then reduced to 5–10 mg/d. Rejection episodes were treated with high-dose steroids initially, and monoclonal antibody therapy (OKT3) was used in patients with steroid resistant rejection.
INITIAL AND FINAL BMD (g/cm2), z SCORES FOR BMD AND BODY COMPOSITION MEASUREMENTS (kg) BEFORE AND FOLLOWING TRANSPLANTATION (MEAN ⫾ SEM)
Bone Mineral Density, Body Composition, and Biochemistry Dual x-ray absorptiometry (DXA) (Lunar Corp, Madison, WI, USA) was used to measure total body and regional BMD and body composition before and after transplantation.14 The regional sites were the lumbar spine, femoral neck, trochanter, and Ward’s triangle. (Ward’s triangle is located at the midbase of the femoral neck, the region with the highest proportion of trabecular bone.) The central:peripheral fat-mass ratio was calculated as truncal fat mass divided by the fat mass of the arms plus the legs. The technique involved the radiation transmission of two discrete energies from an x-ray source. The attenuation of the two energy peaks by soft tissue and bone was quantified. Results were expressed as areal BMD (grams per square centimeter, g/cm2). Measurements were made 3.3 ⫾ 0.7 mo before and 19.3 ⫾ 2.0 mo following transplantation. Measurements of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin were taken in 12 men. Statistical Analysis Paired t tests were used to assess the significance of changes in BMD and body composition. Unpaired t tests were used to determine whether deficits in BMD differed between the men and women and between disease groups. BMD was expressed in absolute terms (g/cm2) and as a z score; the number of standardized deviations (SD) above or below the age-predicted mean. The z score, which adjusts for age and sex, expresses an individual’s BMD on a unit scale where the mean value of the population is zero and about 95% of the population have values between ⫺2 and ⫹2 SD. The z score is the difference between the observed BMD minus the predicted BMD divided by the standard deviation.15 Finding that the group mean BMD z score differs significantly from zero permits rejection of the null hypothesis (that patients with liver disease do not have lower BMD than predicted by their age and gender). RESULTS
BMD results at a mean of 3.3 ⫾ 0.7 mo before and at a mean of 19.3 ⫾ 2.0 mo after transplantation (range 3– 44 mo) are shown
Femoral neck z score Ward’s triangle z score Trochanter z score Lumbar spine z score Total body BMD z score Lean mass (kg) Trunk Legs Arms Total Fat mass (kg) Trunk Legs Arms Total
Before
After
0.91 ⫾ 0.03 ⫺0.47 ⫾ 0.21* 0.77 ⫾ 0.03 ⫺0.35 ⫾ 0.14* 0.77 ⫾ 0.03 ⫺0.56 ⫾ 0.19† 1.06 ⫾ 0.03 ⫺0.76 ⫾ 0.13‡ 1.11 ⫾ 0.01 ⫺0.78 ⫾ 0.15‡
0.83 ⫾ 0.03† ⫺1.2 ⫾ 0.34‡ 0.70 ⫾ 0.03† ⫺0.6 ⫾ 0.15‡ 0.71 ⫾ 0.03* ⫺1.1 ⫾ 0.25‡ 1.03 ⫾ 0.03* ⫺0.9 ⫾ 0.13‡ 1.10 ⫾ 0.01* ⫺0.9 ⫾ 0.14‡
26.1 ⫾ 1.0 15.8 ⫾ 0.6 4.5 ⫾ 0.2 49.3 ⫾ 1.7
24.1 ⫾ 0.7‡ 14.4 ⫾ 0.5‡ 4.7 ⫾ 0.2 46.0 ⫾ 1.3‡
7.2 ⫾ 0.7 6.6 ⫾ 0.7 1.6 ⫾ 0.2 16.5 ⫾ 1.6
14.5 ⫾ 1.1‡ 9.5 ⫾ 0.8‡ 2.4 ⫾ 0.2‡ 27.7 ⫾ 2.0‡
n ⫽ 24 patients for regional bone density measurements. z scores are compared to zero. * P ⱕ 0.05; † P ⱕ 0.01; ‡ P ⱕ 0.001.
in Table I. As shown by the z scores, BMD was reduced by about 0.5 to 0.7 SD at all sites before surgery. Bone loss following transplantation, expressed as a percent of the initial value, is shown in Figure 1. BMD, measured in 24 patients, decreased at all sites: femoral neck 7.7 ⫾ 1.7% (P ⱕ 0.01), Ward’s triangle 9.9 ⫾ 2.5% (P ⱕ 0.01), trochanter 4.2 ⫾ 2.8% (P ⱕ 0.05), and lumbar spine 2.3 ⫾ 1.2% (P ⱕ 0.05). Men had greater bone loss than women at the femoral neck (⫺11.3 ⫾ 2.6% versus ⫺3.9 ⫾ 1.8% [P ⱕ 0.03]). Bone loss was found at the trochanter in men but not in women (⫺8.7 ⫾ 2.4% versus ⫹0.6 ⫾ 5.1% [P ⱕ 0.05]). Fractures of the lumbar spine occurred in one male at 2 and 7 mo and in one female at 3 y posttransplantation. Tramatic fractures to the fifth and ninth ribs occurred in one male. There were no hip fractures in the patients under study. The z scores in the nine patients with cholestatic liver disease (PSC and PBC) were reduced before transplantation (lumbar spine ⫺1.00 ⫾ 0.11 [P ⬍ 0.001], femoral neck ⫺0.68 ⫾ 0.21 [P ⬍ 0.05], Ward’s triangle ⫺0.37 ⫾ 0.13 [P ⬍ 0.05], trochanter ⫺0.64 ⫾ 0.27 [P ⬍ 0.05], total body BMD ⫺1.01 ⫾ 0.18 [P ⬍ 0.001]). There was no detectable difference in BMD between patients with cholestatic versus non-cholestatic liver disease before transplantation except for total body BMD (1.08 ⫾ 0.02 versus 1.14 ⫾ 0.02 g/cm2 respectively [P ⫽ 0.06]). There was no difference in the amount of bone lost following transplantation in patients with cholestatic and non-cholestatic liver disease. Testosterone, LH, FSH, and prolactin measured in 12 of the men at 27 mo following transplant were within the normal range at 13.22 ⫾ 1.92 nmol/L, 25.50 ⫾ 8.90 u/L, 9.76 ⫾ 2.42 u/L, and 3.88 ⫾ 0.43 ng/mL, respectively.
LIVER TRANSPLANTATION AND BONE LOSS AT THE FEMUR
FIG. 1. Percent change in bone density after transplant (all patients). The scale on the y axis is a percentage scale. Mean ⫾ SEM. *, P ⱕ 0.05; †, P ⱕ 0.01.
Body composition before and after transplantation is summarized in Table I. At baseline, body mass index (BMI) was 24.0 ⫾ 0.6 kg/m2. Fat mass was reduced in the men (z score ⫺0.73 ⫾ 0.27 [P ⱕ 0.05]). Lean mass was not reduced before liver transplantation. Total weight increased by 12% following transplantation from 68.5 ⫾ 2.1 to 76.1 ⫾ 2.2 kg (P ⱕ 0.05), leading to an increase in BMI to 26.8 ⫾ 0.8 kg/m2 (P ⱕ 0.001). Weight gain occurred despite a 3.3 ⫾ 0.8 kg decrease in lean mass in the legs and trunk (P ⱕ 0.01) because fat mass increased by 11.2 ⫾ 1.4 kg (P ⱕ 0.01), of which 7.3 ⫾ 0.8 kg gain was truncal and was reflected in a 33% increase in the central:peripheral fat mass ratio (0.95 ⫾ 0.05 to 1.30 ⫾ 0.06 [P ⱕ 0.001]). The change in total body weight and fat mass occurred in women and men. Men had a greater loss of lean mass than women (8.2 ⫾ 2.0% versus 2.7 ⫾ 2.0%, respectively [P ⱕ 0.02]). Before transplantation, patients with PBC and PSC weighed less than patients with liver diseases of other etiologies (63 ⫾ 2.2 kg versus 73 ⫾ 3.0 kg [P ⱕ 0.02]). These patients also had a greater net gain in weight (11.3 ⫾ 1.9 versus 4.5 ⫾ 1.9 kg, respectively, [P ⱕ 0.02]) and lost less lean mass (0.8 ⫾ 1.0 kg versus 5.5 ⫾ 1.1 kg, respectively [P ⱕ 0.01]). DISCUSSION
Rapid bone loss of 3.5–25% following liver transplantation has been reported at the lumbar spine.3,4,6,16 –18 We report that BMD decreased by 4 –10% at the proximal femur during a mean of 19 mo following transplantation—a deficit equivalent to 0.5–1 standard deviations, which doubles the risk of fracture.19 The rate of loss was equivalent to approximately 6%/y, three times greater than the loss of 1–2%/y seen in 60-y-olds.13 Men had three-fold the rate of loss of women at the femoral neck. The reasons for this are not clear. Testosterone deficiency was not present in these subjects. Similar deficits in bone density were seen in cholestatic (PBC and PSC) and non-cholestatic liver disease, indicating that
663
all patients with chronic liver disease awaiting transplantation may be at risk of developing osteoporosis. Bone loss in the elderly accelerates at the proximal femur because increased intracortical porosity and endocortical bone resorption increase the surface area available for resorption in cortical bone which “trabecularizes.”11 In this way, cortical bone contributes more than trabecular bone to the overall loss of bone and predisposes to fractures at cortical sites, such as the proximal femur. Modest changes in lumbar spine BMD may be a consequence of rapid trabecular bone loss early in the disease process because of the greater surface area available for resorption in trabecular bone. As trabeculae perforate and are lost, trabecular surface area decreases with a slowing of the rates of bone loss at the spine. Corticosteroids and cyclosporine therapy may each have contributed to the changes in BMD following liver transplantation. Corticosteroids result in bone loss by reducing bone formation rather than by increasing bone resorption.5,20 The initial changes occur rapidly at the lumbar spine. Bone loss is then detectable later at cortical sites such as the proximal femur.21 Cyclosporine may cause osteopenia in rats.22–24 The osteopenia is characterized by high turnover affecting trabecular bone.5,20,22–27 Cyclosporine may be associated with impairment of testosterone production.20,28,29 Levels of osteocalcin, a marker of bone formation, have been shown to increase after transplantation.30 A trend towards higher BMD in a group of patients treated with cyclosporine but weaned off steroid therapy compared to patients maintained on steroid therapy has been found, suggesting that cyclosporine may have a protective effect on bone.31 We found an overall decrease in lean mass and an increase in total weight and fat mass at 19 mo following transplantation. These changes are most likely to be due to corticosteroid therapy. The reduced muscle mass may reduce muscle strength and predispose to falls. The longevity of transplantation survivors is increasing. These patients require drug therapy known to cause generalized bone loss. There are no data available regarding the long-term effects of liver transplantation on hip fracture rates at this time because of the relatively small numbers of transplantation recipients over 65 y of age. As the numbers of recipients increases and as graft and host survival increases, the incidence of hip fractures is likely to emerge if bone loss is accelerated at this site. The data presented here suggest that patients undergoing successful liver transplantation are at risk for hip fractures due to an increase in bone fragility induced by rapid bone loss and an increased propensity for falls due to reduced muscle mass and strength. The changes we have observed in BMD alone are likely to double fracture risk. The reduction in muscle mass may compound this risk. Hip fractures may be a long-term consequence of liver transplantation and potentially reduce quality of life and longevity. Bone densitometry should be part of the assessment of patients with end-stage liver disease and ongoing management after transplantation. Prophylactic therapy should be considered in patients after liver transplantation, particularly those patients predisposed to fracture by having reduced bone mineral density before surgery. Further studies are needed to identify if recovery in bone mass occurs after liver transplantation, as are studies to examine the pathophysiology and treatment of this problem in women and in men.
REFERENCES 1. Moore KA, Jones RM, Angus P, Hardy K, Burrows G. Psychosocial adjustment to illness: quality of life following liver transplantation. Transplant Proc 1992;24:2257
2. Moore KA, Burrows G, Jones RM, Hardy K. Control evaluation of cognitive functioning, mood state, and quality of life post-liver transplant. Transplant Proc 1992;24:202
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LIVER TRANSPLANTATION AND BONE LOSS AT THE FEMUR
3. Porayko MK, Wiesner RH, Hay JE, et al. Bone disease in liver transplant recipients: incidence, timing and risk factors. Transplant Proc 1991;23:1462 4. Eastell R, Dickson ER, Hodgson SF, et al. Rates of vertebral bone loss before and after liver transplantation in women with primary biliary cirrhosis. Hepatology 1991;14:296 5. Katz IA, Epstein S. Post-transplantation bone disease. J Bone Miner Res 1992;7:123 6. McDonald JA, Dunstan CR, Dilworth P, et al. Bone loss after liver transplantation. Hepatology 1991;14:613 7. Haagsma EB, Thijn CJP, Post JG, Sloof MJH, Gips CH. Bone disease after orthotopic liver transplantation. J Hepatol 1988;6:94 8. Lindor KD. Management of osteopenia of liver disease with special emphasis on primary biliary cirrhosis. Semin Liver Dis 1993;13:367 9. McCaughan GW, Feller RB. Osteoporosis in chronic liver disease: pathogenesis, risk factors, and management. Dig Dis 1994;12:223 10. Hay JE, Dickson ER, Wiesner RH, Krom RAF. Long-term effect of orthotopic liver transplantation on the osteopenia of primary biliary cirrhosis. Hepatology 1990;12:838 11. Foldes J, Parfitt AM, Shin MS, Rao DS, Kleerekoper M. Structural and geometric changes in iliac bone: relationship to normal aging and osteoporosis. J Bone Min Res 1991;6:759 12. Parfitt AM. Skeletal heterogeneity and the purpose of bone remodelling. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San Diego: Academic Press, 1996:315 13. Seeman E, Wahner HW, Offord KP, et al. The differential effects of endocrine dysfunction on the axial and appendicular skeleton. J Clin Invest 1982;69:1302 14. Mazess RB, Wahner HW. Nuclear medicine and densitometry. In: Riggs BL, Melton LJ, eds. Osteoporosis: etiology, diagnosis and management. New York: Raven Press, 1988 15. Seeman E, Hopper JL, Bach LA, et al. Reduced bone mass in daughters of women with osteoporosis. N Engl J Med 1989;320:554 16. Guardiola J, Xiol X, Escriba JM, et al. Osteopenic bone disease in cirrhosis. Changes after transplantation. Hepatology 1994;20:128A 17. Feller RB, McDonald JA, McCaughan GW, Morrow AW. Evidence of bone recovery during long-term follow-up of liver transplant patients. J Gastroenterol Hepatol 1994;9:A78
18. Meys E, Fontanges E, Fourcade N, et al. Bone loss after orthotopic liver transplantation. Am J Med 1994;97:445 19. Melton LJ III, Wahner HW, Richelson LS, O’Fallon WM, Riggs BL. Osteoporosis and the risk of hip fracture. Amer J Epid 1986;124:254 20. Shane E, Epstein S. Immunosuppressive therapy and the skeleton. Trends Endocrinol Metab 1994;5:169 21. Sambrook P, Birmingham J, Kempler S, et al. Corticosteroid effects on proximal femur bone loss. J Bone Miner Res 1990;5:1211 22. Movsowitz C, Epstein S, Fallon M, Ismail F, Thomas S. CyclosporinA in vivo produces severe osteopenia in the rat: effect of dose and duration of administration. Endocrinology 1988;123:2571 23. Movsowitz C, Epstein S, Ismail F, Fallon M, Thomas S. Cyclosporin A in the oophorectomized rat: unexpected severe bone resorption. J Bone Min Res 1989;4:393 24. Schloberg M, Movsowitz C, Epstein S, et al. The effect of cyclosporin A administration and its withdrawal on bone mineral metabolism in the rat. Endocrinology 1989;24:2179 25. Cvetkovic M, Mann GN, Romero DF, et al. The deleterious effects of long-term cyclosporine A, cyclosporine G, and FK506 on bone mineral metabolism in vivo. Transplantation 1994;57:1231 26. Stein B, Takizawa M, Schlosberg M, et al. Evidence that cyclosporine G is less deleterious to rat bone in vivo than cyclosporine A. Transplantation 1992;53:628 27. Jacobs TW, Katz IA, Joffe II, et al. The effect of FK 506, cyclosporine A, and cyclosporine G on serum 1,25-dihydroxyvitamin D levels. Transplantation Proc 1991;23:3188 28. Seethalakshmi L, Menon M, Malhotra RA, Diamond DA. Effect of cyclosporine A on male reproduction in rats. J Urol 1987;138:991 29. Ramirez G, Narvarte J, Bittle PA, Ayers-Chastain C, Dean SE. Cyclosporine-induced alterations in the hypothalamic hypophyseal gonadal axis in transplant patients. Nephron 1991;58:27 30. Watson RG, Coulton L, Kanis JA, et al. Circulating osteocalcin in primary biliary cirrhosis following liver transplantation and during treatment with cyclosporin. J Hepatol 1990;11:354 31. Wolpaw T, Deal CL, Fleming-Brooks S, et al. Factors influencing vertebral bone density after renal transplantation. Transplantation 1994;58:1186
Nutrition Vol. 15, No. 9, 1999
Bone Loss at the Proximal Femur and Reduced Lean Mass Following Liver Transplantation: A Longitudinal Study JENNIFER B. KEOGH, MSC,* CON TSALAMANDRIS, MBBS,† RICHARD B. SEWELL, MD,‡ ROBERT M. JONES, FRACS,§ PETER W. ANGUS, MD,‡ IBOLYA B. NYULASI, MSC,* AND EGO SEEMAN, MD† From the Departments of *Nutrition and Dietetics, †Endocrinology, ‡Gastroenterology, and §Surgery, Austin and Repatriation Medical Centre, Melbourne, Australia ABSTRACT
The longevity of recipients of liver transplant may be compromised by spinal osteoporosis and vertebral fractures. However, femoral neck fractures are associated with a higher morbidity and mortality than spine fractures. As there is little information on bone loss at this clinically important site of fracture, the aim of this study was to determine whether accelerated bone loss occurs at the proximal femur following transplantation. Bone mineral density and body composition were measured at the femoral neck, lumbar spine and total body, using dual x-ray absorptiometry in 22 men and 19 women, age 46 ⫾ 1.4 y (mean ⫾ SEM) before and at a mean of 19 mo after surgery (range 3– 44). Results were expressed in absolute terms (g/cm2) and as a z score. Before transplantation, z scores for bone mineral density were reduced at the femoral neck (⫺0.47 ⫾ 0.21 SD), trochanter (⫺0.56 ⫾ 0.19 SD), Ward’s triangle (⫺0.35 ⫾ 0.14 SD), lumbar spine (⫺0.76 ⫾ 0.13 SD), and total body (⫺0.78 ⫾ 0.15 SD) (all P ⬍ 0.01 to ⬍ 0.001). Following transplantation, bone mineral density decreased by 8.0 ⫾ 1.7% at the femoral neck (P ⱕ 0.01) and by 2.0 ⫾ 1.2% at the lumbar spine (P ⱕ 0.05). Total weight increased by 12.2 ⫾ 2.3%, lean mass decreased by 5.7 ⫾ 1.4%, while fat mass increased from 24.1 ⫾ 2.0% to 35.1 ⫾ 1.8% (all P ⱕ 0.001). Patients with end-stage liver disease have reduced bone mineral density. Liver transplantation is associated with a rapid decrease in bone mineral density at the proximal femur, further increasing fracture risk and a reduction in lean (muscle) mass, which may also predispose to falls. Prophylactic therapy to prevent further bone loss should be considered in patients after liver transplantation. Nutrition 1999;15:661– 664. ©Elsevier Science Inc. 1999 Key words: bone mineral density, liver transplantation, femoral neck fractures, body composition
INTRODUCTION
The short- and long-term survival after liver transplantation is excellent and attention has now been directed at quality of life and the potential long-term complications following successful transplant surgery.1,2 One important long-term clinical problem is osteoporosis. Osteoporosis has been documented in patients with end-stage liver disease before transplantation and accelerated bone loss at the lumbar spine has been reported following transplantation, with spine fractures occurring in 17– 65% of patients in the first 12 mo after transplantation.2–10 This occurrence of bone loss at the spine early in disease is a consequence of the high proportion of trabecular bone in the vertebral body. Trabecular bone has a higher surface-to-volume ratio than cortical bone. This trabecular surface is in close proximity to the marrow in the vertebral body so that bone loss, a
surface phenomenon, occurs more rapidly at trabecular sites predisposing to the earlier emergence of bone fragility at this site.11 By contrast, the proximal femur is predominantly cortical and contains a less cellular marrow than the vertebral body.12 Both of these characteristics are likely to contribute to the slower rate of bone loss at this site seen during aging and following exposure to corticosteroids.13 The effects of liver transplantation on bone mineral density (BMD) at the proximal femur have not been well described. A high rate of bone loss at this site will predispose to hip fractures, with attendant high morbidity and mortality. The aim of this study was to document whether accelerated bone loss occurs at the proximal femur and whether muscle mass decreases following transplantation, since decreased muscle mass may predispose to falls and hip fracture. The results of this study draw attention to the increased risk of hip fracture in these patients.
Correspondence to: Jennifer B. Keogh, MSc, Nutrition Department, Alfred Hospital, P.O. Box 315, Prahran, Melbourne 3181, Australia.
Nutrition 15:661– 664, 1999 ©Elsevier Science Inc. 1999 Printed in the USA. All rights reserved.
0899-9007/99/$20.00 PII S0899-9007(99)00121-5
662
LIVER TRANSPLANTATION AND BONE LOSS AT THE FEMUR MATERIALS AND METHODS
TABLE I.
Patients BMD and body composition were measured as part of the liver transplantation assessment protocol of the Victorian Liver Transplant Unit and ongoing clinical management of transplant recipients. Data were available for 41 patients with end-stage liver disease who underwent liver transplantation between 1988 and 1994. There were 22 men and 19 women with a mean age of 46 ⫾ 1.4 y (range 25– 66). The etiology of liver disease included primary sclerosing cholangitis (PSC) (12), primary biliary cirrhosis (PBC) (6), chronic active hepatitis (5), alcoholic cirrhosis (5), autoimmune chronic active hepatitis (5), secondary malignancy (1), Wilson’s disease (2), cryptogenic cirrhosis (1), secondary biliary cirrhosis (1), acute hepatic necrosis (1), chronic BuddChiari syndrome (1), and hemachromatosis (1). Of the 19 women, 11 were postmenopausal at the time of transplant and a further 3 experienced menopause in the time between transplant and repeat DXA measurement. All patients were treated with cyclosporine, prednisolone, and azathioprine following transplantation. Prednisolone was commenced at 200 mg/d. The dose was reduced by day 5 to 20 mg/d for 3 mo, and then reduced to 5–10 mg/d. Rejection episodes were treated with high-dose steroids initially, and monoclonal antibody therapy (OKT3) was used in patients with steroid resistant rejection.
INITIAL AND FINAL BMD (g/cm2), z SCORES FOR BMD AND BODY COMPOSITION MEASUREMENTS (kg) BEFORE AND FOLLOWING TRANSPLANTATION (MEAN ⫾ SEM)
Bone Mineral Density, Body Composition, and Biochemistry Dual x-ray absorptiometry (DXA) (Lunar Corp, Madison, WI, USA) was used to measure total body and regional BMD and body composition before and after transplantation.14 The regional sites were the lumbar spine, femoral neck, trochanter, and Ward’s triangle. (Ward’s triangle is located at the midbase of the femoral neck, the region with the highest proportion of trabecular bone.) The central:peripheral fat-mass ratio was calculated as truncal fat mass divided by the fat mass of the arms plus the legs. The technique involved the radiation transmission of two discrete energies from an x-ray source. The attenuation of the two energy peaks by soft tissue and bone was quantified. Results were expressed as areal BMD (grams per square centimeter, g/cm2). Measurements were made 3.3 ⫾ 0.7 mo before and 19.3 ⫾ 2.0 mo following transplantation. Measurements of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin were taken in 12 men. Statistical Analysis Paired t tests were used to assess the significance of changes in BMD and body composition. Unpaired t tests were used to determine whether deficits in BMD differed between the men and women and between disease groups. BMD was expressed in absolute terms (g/cm2) and as a z score; the number of standardized deviations (SD) above or below the age-predicted mean. The z score, which adjusts for age and sex, expresses an individual’s BMD on a unit scale where the mean value of the population is zero and about 95% of the population have values between ⫺2 and ⫹2 SD. The z score is the difference between the observed BMD minus the predicted BMD divided by the standard deviation.15 Finding that the group mean BMD z score differs significantly from zero permits rejection of the null hypothesis (that patients with liver disease do not have lower BMD than predicted by their age and gender). RESULTS
BMD results at a mean of 3.3 ⫾ 0.7 mo before and at a mean of 19.3 ⫾ 2.0 mo after transplantation (range 3– 44 mo) are shown
Femoral neck z score Ward’s triangle z score Trochanter z score Lumbar spine z score Total body BMD z score Lean mass (kg) Trunk Legs Arms Total Fat mass (kg) Trunk Legs Arms Total
Before
After
0.91 ⫾ 0.03 ⫺0.47 ⫾ 0.21* 0.77 ⫾ 0.03 ⫺0.35 ⫾ 0.14* 0.77 ⫾ 0.03 ⫺0.56 ⫾ 0.19† 1.06 ⫾ 0.03 ⫺0.76 ⫾ 0.13‡ 1.11 ⫾ 0.01 ⫺0.78 ⫾ 0.15‡
0.83 ⫾ 0.03† ⫺1.2 ⫾ 0.34‡ 0.70 ⫾ 0.03† ⫺0.6 ⫾ 0.15‡ 0.71 ⫾ 0.03* ⫺1.1 ⫾ 0.25‡ 1.03 ⫾ 0.03* ⫺0.9 ⫾ 0.13‡ 1.10 ⫾ 0.01* ⫺0.9 ⫾ 0.14‡
26.1 ⫾ 1.0 15.8 ⫾ 0.6 4.5 ⫾ 0.2 49.3 ⫾ 1.7
24.1 ⫾ 0.7‡ 14.4 ⫾ 0.5‡ 4.7 ⫾ 0.2 46.0 ⫾ 1.3‡
7.2 ⫾ 0.7 6.6 ⫾ 0.7 1.6 ⫾ 0.2 16.5 ⫾ 1.6
14.5 ⫾ 1.1‡ 9.5 ⫾ 0.8‡ 2.4 ⫾ 0.2‡ 27.7 ⫾ 2.0‡
n ⫽ 24 patients for regional bone density measurements. z scores are compared to zero. * P ⱕ 0.05; † P ⱕ 0.01; ‡ P ⱕ 0.001.
in Table I. As shown by the z scores, BMD was reduced by about 0.5 to 0.7 SD at all sites before surgery. Bone loss following transplantation, expressed as a percent of the initial value, is shown in Figure 1. BMD, measured in 24 patients, decreased at all sites: femoral neck 7.7 ⫾ 1.7% (P ⱕ 0.01), Ward’s triangle 9.9 ⫾ 2.5% (P ⱕ 0.01), trochanter 4.2 ⫾ 2.8% (P ⱕ 0.05), and lumbar spine 2.3 ⫾ 1.2% (P ⱕ 0.05). Men had greater bone loss than women at the femoral neck (⫺11.3 ⫾ 2.6% versus ⫺3.9 ⫾ 1.8% [P ⱕ 0.03]). Bone loss was found at the trochanter in men but not in women (⫺8.7 ⫾ 2.4% versus ⫹0.6 ⫾ 5.1% [P ⱕ 0.05]). Fractures of the lumbar spine occurred in one male at 2 and 7 mo and in one female at 3 y posttransplantation. Tramatic fractures to the fifth and ninth ribs occurred in one male. There were no hip fractures in the patients under study. The z scores in the nine patients with cholestatic liver disease (PSC and PBC) were reduced before transplantation (lumbar spine ⫺1.00 ⫾ 0.11 [P ⬍ 0.001], femoral neck ⫺0.68 ⫾ 0.21 [P ⬍ 0.05], Ward’s triangle ⫺0.37 ⫾ 0.13 [P ⬍ 0.05], trochanter ⫺0.64 ⫾ 0.27 [P ⬍ 0.05], total body BMD ⫺1.01 ⫾ 0.18 [P ⬍ 0.001]). There was no detectable difference in BMD between patients with cholestatic versus non-cholestatic liver disease before transplantation except for total body BMD (1.08 ⫾ 0.02 versus 1.14 ⫾ 0.02 g/cm2 respectively [P ⫽ 0.06]). There was no difference in the amount of bone lost following transplantation in patients with cholestatic and non-cholestatic liver disease. Testosterone, LH, FSH, and prolactin measured in 12 of the men at 27 mo following transplant were within the normal range at 13.22 ⫾ 1.92 nmol/L, 25.50 ⫾ 8.90 u/L, 9.76 ⫾ 2.42 u/L, and 3.88 ⫾ 0.43 ng/mL, respectively.
LIVER TRANSPLANTATION AND BONE LOSS AT THE FEMUR
FIG. 1. Percent change in bone density after transplant (all patients). The scale on the y axis is a percentage scale. Mean ⫾ SEM. *, P ⱕ 0.05; †, P ⱕ 0.01.
Body composition before and after transplantation is summarized in Table I. At baseline, body mass index (BMI) was 24.0 ⫾ 0.6 kg/m2. Fat mass was reduced in the men (z score ⫺0.73 ⫾ 0.27 [P ⱕ 0.05]). Lean mass was not reduced before liver transplantation. Total weight increased by 12% following transplantation from 68.5 ⫾ 2.1 to 76.1 ⫾ 2.2 kg (P ⱕ 0.05), leading to an increase in BMI to 26.8 ⫾ 0.8 kg/m2 (P ⱕ 0.001). Weight gain occurred despite a 3.3 ⫾ 0.8 kg decrease in lean mass in the legs and trunk (P ⱕ 0.01) because fat mass increased by 11.2 ⫾ 1.4 kg (P ⱕ 0.01), of which 7.3 ⫾ 0.8 kg gain was truncal and was reflected in a 33% increase in the central:peripheral fat mass ratio (0.95 ⫾ 0.05 to 1.30 ⫾ 0.06 [P ⱕ 0.001]). The change in total body weight and fat mass occurred in women and men. Men had a greater loss of lean mass than women (8.2 ⫾ 2.0% versus 2.7 ⫾ 2.0%, respectively [P ⱕ 0.02]). Before transplantation, patients with PBC and PSC weighed less than patients with liver diseases of other etiologies (63 ⫾ 2.2 kg versus 73 ⫾ 3.0 kg [P ⱕ 0.02]). These patients also had a greater net gain in weight (11.3 ⫾ 1.9 versus 4.5 ⫾ 1.9 kg, respectively, [P ⱕ 0.02]) and lost less lean mass (0.8 ⫾ 1.0 kg versus 5.5 ⫾ 1.1 kg, respectively [P ⱕ 0.01]). DISCUSSION
Rapid bone loss of 3.5–25% following liver transplantation has been reported at the lumbar spine.3,4,6,16 –18 We report that BMD decreased by 4 –10% at the proximal femur during a mean of 19 mo following transplantation—a deficit equivalent to 0.5–1 standard deviations, which doubles the risk of fracture.19 The rate of loss was equivalent to approximately 6%/y, three times greater than the loss of 1–2%/y seen in 60-y-olds.13 Men had three-fold the rate of loss of women at the femoral neck. The reasons for this are not clear. Testosterone deficiency was not present in these subjects. Similar deficits in bone density were seen in cholestatic (PBC and PSC) and non-cholestatic liver disease, indicating that
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all patients with chronic liver disease awaiting transplantation may be at risk of developing osteoporosis. Bone loss in the elderly accelerates at the proximal femur because increased intracortical porosity and endocortical bone resorption increase the surface area available for resorption in cortical bone which “trabecularizes.”11 In this way, cortical bone contributes more than trabecular bone to the overall loss of bone and predisposes to fractures at cortical sites, such as the proximal femur. Modest changes in lumbar spine BMD may be a consequence of rapid trabecular bone loss early in the disease process because of the greater surface area available for resorption in trabecular bone. As trabeculae perforate and are lost, trabecular surface area decreases with a slowing of the rates of bone loss at the spine. Corticosteroids and cyclosporine therapy may each have contributed to the changes in BMD following liver transplantation. Corticosteroids result in bone loss by reducing bone formation rather than by increasing bone resorption.5,20 The initial changes occur rapidly at the lumbar spine. Bone loss is then detectable later at cortical sites such as the proximal femur.21 Cyclosporine may cause osteopenia in rats.22–24 The osteopenia is characterized by high turnover affecting trabecular bone.5,20,22–27 Cyclosporine may be associated with impairment of testosterone production.20,28,29 Levels of osteocalcin, a marker of bone formation, have been shown to increase after transplantation.30 A trend towards higher BMD in a group of patients treated with cyclosporine but weaned off steroid therapy compared to patients maintained on steroid therapy has been found, suggesting that cyclosporine may have a protective effect on bone.31 We found an overall decrease in lean mass and an increase in total weight and fat mass at 19 mo following transplantation. These changes are most likely to be due to corticosteroid therapy. The reduced muscle mass may reduce muscle strength and predispose to falls. The longevity of transplantation survivors is increasing. These patients require drug therapy known to cause generalized bone loss. There are no data available regarding the long-term effects of liver transplantation on hip fracture rates at this time because of the relatively small numbers of transplantation recipients over 65 y of age. As the numbers of recipients increases and as graft and host survival increases, the incidence of hip fractures is likely to emerge if bone loss is accelerated at this site. The data presented here suggest that patients undergoing successful liver transplantation are at risk for hip fractures due to an increase in bone fragility induced by rapid bone loss and an increased propensity for falls due to reduced muscle mass and strength. The changes we have observed in BMD alone are likely to double fracture risk. The reduction in muscle mass may compound this risk. Hip fractures may be a long-term consequence of liver transplantation and potentially reduce quality of life and longevity. Bone densitometry should be part of the assessment of patients with end-stage liver disease and ongoing management after transplantation. Prophylactic therapy should be considered in patients after liver transplantation, particularly those patients predisposed to fracture by having reduced bone mineral density before surgery. Further studies are needed to identify if recovery in bone mass occurs after liver transplantation, as are studies to examine the pathophysiology and treatment of this problem in women and in men.
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2. Moore KA, Burrows G, Jones RM, Hardy K. Control evaluation of cognitive functioning, mood state, and quality of life post-liver transplant. Transplant Proc 1992;24:202
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3. Porayko MK, Wiesner RH, Hay JE, et al. Bone disease in liver transplant recipients: incidence, timing and risk factors. Transplant Proc 1991;23:1462 4. Eastell R, Dickson ER, Hodgson SF, et al. Rates of vertebral bone loss before and after liver transplantation in women with primary biliary cirrhosis. Hepatology 1991;14:296 5. Katz IA, Epstein S. Post-transplantation bone disease. J Bone Miner Res 1992;7:123 6. McDonald JA, Dunstan CR, Dilworth P, et al. Bone loss after liver transplantation. Hepatology 1991;14:613 7. Haagsma EB, Thijn CJP, Post JG, Sloof MJH, Gips CH. Bone disease after orthotopic liver transplantation. J Hepatol 1988;6:94 8. Lindor KD. Management of osteopenia of liver disease with special emphasis on primary biliary cirrhosis. Semin Liver Dis 1993;13:367 9. McCaughan GW, Feller RB. Osteoporosis in chronic liver disease: pathogenesis, risk factors, and management. Dig Dis 1994;12:223 10. Hay JE, Dickson ER, Wiesner RH, Krom RAF. Long-term effect of orthotopic liver transplantation on the osteopenia of primary biliary cirrhosis. Hepatology 1990;12:838 11. Foldes J, Parfitt AM, Shin MS, Rao DS, Kleerekoper M. Structural and geometric changes in iliac bone: relationship to normal aging and osteoporosis. J Bone Min Res 1991;6:759 12. Parfitt AM. Skeletal heterogeneity and the purpose of bone remodelling. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San Diego: Academic Press, 1996:315 13. Seeman E, Wahner HW, Offord KP, et al. The differential effects of endocrine dysfunction on the axial and appendicular skeleton. J Clin Invest 1982;69:1302 14. Mazess RB, Wahner HW. Nuclear medicine and densitometry. In: Riggs BL, Melton LJ, eds. Osteoporosis: etiology, diagnosis and management. New York: Raven Press, 1988 15. Seeman E, Hopper JL, Bach LA, et al. Reduced bone mass in daughters of women with osteoporosis. N Engl J Med 1989;320:554 16. Guardiola J, Xiol X, Escriba JM, et al. Osteopenic bone disease in cirrhosis. Changes after transplantation. Hepatology 1994;20:128A 17. Feller RB, McDonald JA, McCaughan GW, Morrow AW. Evidence of bone recovery during long-term follow-up of liver transplant patients. J Gastroenterol Hepatol 1994;9:A78
18. Meys E, Fontanges E, Fourcade N, et al. Bone loss after orthotopic liver transplantation. Am J Med 1994;97:445 19. Melton LJ III, Wahner HW, Richelson LS, O’Fallon WM, Riggs BL. Osteoporosis and the risk of hip fracture. Amer J Epid 1986;124:254 20. Shane E, Epstein S. Immunosuppressive therapy and the skeleton. Trends Endocrinol Metab 1994;5:169 21. Sambrook P, Birmingham J, Kempler S, et al. Corticosteroid effects on proximal femur bone loss. J Bone Miner Res 1990;5:1211 22. Movsowitz C, Epstein S, Fallon M, Ismail F, Thomas S. CyclosporinA in vivo produces severe osteopenia in the rat: effect of dose and duration of administration. Endocrinology 1988;123:2571 23. Movsowitz C, Epstein S, Ismail F, Fallon M, Thomas S. Cyclosporin A in the oophorectomized rat: unexpected severe bone resorption. J Bone Min Res 1989;4:393 24. Schloberg M, Movsowitz C, Epstein S, et al. The effect of cyclosporin A administration and its withdrawal on bone mineral metabolism in the rat. Endocrinology 1989;24:2179 25. Cvetkovic M, Mann GN, Romero DF, et al. The deleterious effects of long-term cyclosporine A, cyclosporine G, and FK506 on bone mineral metabolism in vivo. Transplantation 1994;57:1231 26. Stein B, Takizawa M, Schlosberg M, et al. Evidence that cyclosporine G is less deleterious to rat bone in vivo than cyclosporine A. Transplantation 1992;53:628 27. Jacobs TW, Katz IA, Joffe II, et al. The effect of FK 506, cyclosporine A, and cyclosporine G on serum 1,25-dihydroxyvitamin D levels. Transplantation Proc 1991;23:3188 28. Seethalakshmi L, Menon M, Malhotra RA, Diamond DA. Effect of cyclosporine A on male reproduction in rats. J Urol 1987;138:991 29. Ramirez G, Narvarte J, Bittle PA, Ayers-Chastain C, Dean SE. Cyclosporine-induced alterations in the hypothalamic hypophyseal gonadal axis in transplant patients. Nephron 1991;58:27 30. Watson RG, Coulton L, Kanis JA, et al. Circulating osteocalcin in primary biliary cirrhosis following liver transplantation and during treatment with cyclosporin. J Hepatol 1990;11:354 31. Wolpaw T, Deal CL, Fleming-Brooks S, et al. Factors influencing vertebral bone density after renal transplantation. Transplantation 1994;58:1186