Since the advent of liver transplantation more than

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1 Serial Measurements of Bone Density at the Lumbar Spine Do Not Predict Fracture Risk After Liver Transplantation Karen L. Hardinger, * Bing Ho, Mark A. Schnitzler, Niraj Desai, Jeffrey Lowell, Surendra Shenoy, William Chapman, and Jeffrey S. Crippin Bone disease has emerged as a serious and complex complication after liver transplantation. The purpose of this study is to determine risk factors for fracture and bone loss after liver transplantation. Dual-energy x-ray absorptiometry (DEXA) of the lumbar spine was performed routinely pretransplantation, 6 months posttransplantation, and at yearly intervals thereafter at our center. We followed up patients who underwent transplantation in the past 10 years and compared bone mineral density (BMD) and fracture rate with known risk factors for bone loss in primary transplant recipients who met the inclusion criteria of a pretransplantation DEXA and at least one follow-up DEXA scan postoperatively (n 153). We observed a 15% (n 23) prevalence of symptomatic fractures at a mean of years after transplantation. Change in BMD was greatest from pretransplantation to 6 months posttransplantation ( 4.2%; P.006), then increased at a rate of 1.4% per year. Logistic regression analysis showed an association of fracture risk with several factors, including number of acute rejection episodes (P.045), smoking (P.02), and female sex (P.02). Stepwise logistic regression analysis reported female sex (P.004) as the only factor associated with fracture after transplantation. Age, time listed for transplantation, race, menopause, chronic renal insufficiency, loss of height, family history of osteoporosis, BMD, and T score did not predict fracture or bone loss after transplantation. In conclusion, serial measurements of BMD at the lumbar spine do not appear to predict fracture risk; however, data suggest that female sex is the strongest predictor of fracture after liver transplantation. (Liver Transpl 2003;9: ) Since the advent of liver transplantation more than two decades ago, there has been a steady evolution of care focusing on the major outcomes of immediate patient and allograft survival. These remain the primary benchmarks of success in any active transplant program. However, with routine long-term survival in excess of 10 to 15 years, posttransplantation medicine has become an emerging and complicated subspecialty. Osteoporosis has shown itself as an important issue in posttransplantation care. The prevalence of bone fractures after orthotopic liver transplantation ranges from 15% to 50%. 1-6 Significant bone loss is apparent before and after transplantation. The impact of liver disease on bone mineral density (BMD) before transplantation has been documented. 7,8 Diamond et al 7 showed osteoporotic changes in 21% of patients, and Bonkovsky et al 8 showed a prevalence of decreased BMD ranging from 10% to 56%, depending on the cause of liver failure. It appears that patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) are at the greatest risk for pretransplantation osteoporosis. The impact of transplantation on short-term (1 to 3 years) bone loss after transplantation also has been documented. 1,9-14 The collective experience from these studies indicates that patients undergoing liver transplantation appear to have lower average BMDs than average, and BMD appears to decline dramatically in the 3 to 6 months after transplantation. In the 6- to 12-month period after transplantation, BMD appears to improve. No clear risk factors for fractures after transplantation have been identified. Furthermore, the correlation between BMD and risk for fracture in liver transplant recipients has not been shown in any study to date. The long-term effect of bone mineral loss in liver transplant recipients is poorly understood. One recent study reports up to 15 years of follow-up in a small number of patients. 15 Because many controversies still exist about the extent, severity, risk factors, and actual incidence of osteopenia and fractures after liver transplantation, this study is designed to examine these issues further. Methods This retrospective study assessed patients at a single center who received liver transplants during a 10-year period From the Departments of *Pharmacy, Medicine, and Surgery, and the Health Administration Program, Barnes-Jewish Hospital/Washington University School of Medicine, St Louis, MO. Address reprint requests to Jeffrey S. Crippin, MD, Medical Director, Liver Transplantation, Barnes-Jewish Hospital, 216 S Kingshighway, St Louis, MO Telephone: ; FAX: ; jcrippin@im.wustl.edu Copyright 2003 by the American Association for the Study of Liver Diseases /03/ $30.00/0 doi: /jlts Liver Transplantation, Vol 9, No 8 (August), 2003: pp

2 858 Hardinger et al between January 1991 and December 2000 (n 457). Inclusion criteria are defined as first transplant, a minimum of 6 months of follow-up, baseline dual-energy x-ray absorptiometry (DEXA) at our institution, and at least one DEXA after transplantation at our institution (n 153). BMD and rate of fracture were compared with known risk factors for bone loss. Fracture Assessment and BMD Measurement Fractures were identified by patient questionnaire and verified by radiological evidence. Pretransplantation DEXA of the lumbar spine was compared with scans at 6 months posttransplantation, 1 year posttransplantation, and annually thereafter. All DEXA scans were performed using the Hologic QDR densitometer (Hologic Inc, Bedford, MA). Instruments were calibrated daily. Lumbar spine measurement was conducted with an anteroposterior view between L2 and L4 and expressed as BMD in grams per centimeter squared. BMD was compared with bone mass of young healthy adults using the T score, the number of SDs above (positive) or below (negative) the average peak bone mass of young healthy controls of the same race and sex. Osteopenia and osteoporosis are defined according the World Health Organization classification. 16 Immunosuppression Cyclosporine therapy was initiated at 6 to 8 mg/kg/d orally in two divided doses, with 12-hour maintenance trough concentrations targeted at 250 to 350 ng/ml by monoclonal fluorescent polarization immunoassay (Abbott Laboratories, Abbott Park, IL) immediately after transplantation. At 3 to 6 months, posttransplantation concentrations were reduced to 150 to 250 mg/dl. Methylprednisolone, 500 mg, was administered intraoperatively, followed by a 6-day taper of corticosteroids to oral prednisone at a dose of 20 mg/d. Prednisone taper was adjusted based on the patient s clinical course. Calcium carbonate (1 to 1.5 g/d) was prescribed to all patients after transplantation. Calcium, vitamin D, hormone replacement therapy, and bisphosphonate use after transplantation was recorded. Patients who showed clinical or biopsy-proven acute rejection routinely were administered 1 g of methylprednisolone intravenously, followed by an oral steroid recycle. Risk Factors for Fracture and Osteoporosis Throughout the study period, patients completed a questionnaire at the time of each DEXA scan. The questionnaire included demographic information, as well as questions about medications, family history, smoking status, loss of height, fracture occurrence, and menopausal status, if applicable. Additional data collected included type of liver failure, time listed for transplantation, pretransplantation albumin level, date of transplantation, chronic renal insufficiency (defined as a serum creatinine level 2.0 mg/dl at two occasions 6 months apart), acute rejection episodes, and treatment for acute rejection. Medications before and after transplantation were identified. Data Analysis Differences in characteristics of patients were tested using Student s t-test for continuous variables, Fisher s exact test for binary categorical variables, Chi-squared for multicategorical variables, and Mantel-Haenszel Chi-squared for ordered multicategorical variables. Stepwise variable selection techniques were used for all multivariate estimates. All statistical tests were two-tailed. P was required to be less than.05 for significance. Results Patient Demographics and Characteristics Mean patient age at the time of transplantation was years (Table 1). Patients were mostly white (92%), and hepatitis C was the most common cause of end-stage liver disease. Eighty-one percent of women were postmenopausal. Most patients reported the use of calcium posttransplantation (75%). Other treatments administered for bone loss, based on clinical judgment, included estrogen (14%) and alendronate (12%). Posttransplantation patients were administered cyclosporine and prednisone, with tapering doses over time. Median daily prednisone dose decreased over time: 7.5 mg/d at 6 months, 5 mg/d at 1 year, 5 mg/d at 2 years, 5 mg/d at 3 years, 2.5 mg/d at 4 years, and 2.5 mg/d at 5 years posttransplantation. More than half the patients had the steroid dose tapered by 5 years after transplantation. Median cumulative steroid dose was 10.6 g, and mean follow-up posttransplantation was years. Fractures We observed a 15% (n 23) prevalence of fractures, which was greater in women (24%) than men (8%; P.002). Mean time to fracture was years. Fractures occurred at the hip (n 4), rib (n 6), and appendicular skeleton (n 13). The prevalence of risk factors for fracture is listed in Table 2. Univariate analysis associated female sex (P.01), PBC (P.001), and number of acute rejection episodes per patient (P.01) with fracture. Age, race, pretransplantation albumin level, time listed for transplantation, menopause, chronic renal insufficiency (serum creatinine 2.0 mg/dl at two occasions 6 months apart), smoking history, loss of height, height, steroid dose, and bone mineral loss assessed by DEXA did not predict fracture. Logistic regression analysis including all risk factors for fracture showed an association of fracture with several

3 Bone Density Following Liver Transplantation 859 Table 1. Patient Demographics and Risk Factors Mean age (yr) Men 79 (52) Women 74 (48) White 140 (92) Black 13 (8) Disease leading to transplantation Hepatitis C 33 (22) Alcoholic liver disease 29 (19) PBC 28 (18) Cryptogenic 20 (13) PSC 20 (13) Autoimmune 7 (5) Hepatitis B virus 5 (3) Other 11 (7) Age at menopause (yr) Menopausal patients 60 (81) Chronic renal insufficiency 36 (24) Smoking history 68 (44) Family history of osteoporosis 29 (19) Loss of height posttransplantation 16 (10) Height (inches) Acute rejection episodes per patient No of patients with rejection 60 (40) Total rejection episodes (total of 93) 1 Lifetime steroid dose (g) 12 5 Listed time pretransplantation (yr) Mean follow-up posttransplantation (yr) NOTE. N 153. Values expressed as mean SD or number (percent). factors, including number of acute rejection episodes (P.045), any acute rejection episode (P.06), smoking (P.02), and female sex (P.02). Stepwise logistic regression analysis found female sex (P.004) as the only factor associated with fracture after transplantation. BMD A total of 713 DEXA scans were performed during the study period, or an average of 5 scans per patient. Percentage of change in BMD was greatest from pretransplantation to 6 months posttransplantation ( g/cm 2 pretransplantation v g/cm 2 at 6 months). The rate of change during this period was 4.2% (P.006; Fig. 1). After 6 months posttransplantation, BMD increased at a rate of 1.4% per year. Significant bone loss was seen in our patients compared with healthy young controls. The percentage of patients with osteopenia (defined as a T score 1.0) pretransplantation was 50% and increased to 63% at 6 months posttransplantation (Fig. 2). By 1 year posttransplantation, the number of patients with osteopenia was similar to that pretransplantation (54%). Likewise, percentages of patients with osteoporosis (defined as a T score 2.5) were 17% pretransplantation, 28% at 6 months posttransplantation, and 16% at 1 year posttransplantation. Univariate analysis associated bone loss after transplantation and increased height (P.05), cholestatic liver disease (P.05), patients with acute rejection (P.001), and cumulative steroid dose (P.01). Age, race, time listed for transplantation, pretransplantation albumin level, menopause, chronic renal insufficiency, family history of osteoporosis, loss of height, steroid dose, and number of acute rejection episodes did not predict osteopenia. Serial BMD and T score did not predict fracture, although a low T score ( 1.5) at baseline was associated with osteopenia at 6 months (P.001) and 1 year (P.001) after transplantation. Increased height was the only factor associated with bone loss after transplantation in multivariate analysis (P.03). Stepwise logistic regression associated osteopenia at 6 months after transplantation with sex (P.001), pretransplantation DEXA score (P.001), and loss of height (P.036). Osteopenia at 1 year after transplantation was associated with pretransplantation DEXA score (P.001) and sex (P.047). Osteopenia at 2 years after transplantation was associated only with pretransplantation DEXA score (P.001). Patients with evidence of osteopenia pretransplantation (n 77) did not lose bone mass at 6 months posttransplantation (BMD pretransplantation, v g/cm 2 posttransplantation; P not significant), whereas patients without evidence of osteopenia pretransplantation (n 76) lost bone mass at 6 months posttransplantation (BMD pretransplantation, v g/cm 2 posttransplantation; P.004). Patients with cholestatic liver disease and fracture had significantly lower BMD pretransplantation ( g/cm 2 ) than patients with cholestatic liver disease who did not have fracture ( g/cm 2 ; P.03). Pretransplantation T score was in the group with cholestatic liver disease and fracture and in the group with cholestatic disease and no fracture. Risk factors for pretransplantation osteoporosis included female sex (P.047) and chronic renal insufficiency (P.006). Alcoholic hepatitis was less com-

4 860 Hardinger et al Table 2. Univariate Analysis of Risk Factors for Fracture Characteristic Fracture (n 23) No Fracture (n 130) Men (n 79) Women (n 74) Mean age (yr) Men 5 (22) 74 (57) Women 18 (78) 56 (43)* White 22 (96) 118 (91) 73 (92) 67 (91) Black 1 (4) 12 (9) 6 (8) 7 (8) Cause of end-stage liver disease Autoimmune Alcoholic liver disease 0 29* 25 4 Viral hepatitis PBC PSC Other/unknown Cholestatic (vs noncholestatic) Menopausal patients 15 (83) 46 (82) Chronic renal insufficiency 5 (22) 31 (24) 20 (25) 16 (22) Smoking history 12 (52) 56 (43) 43 (54) 25 (34) Family history of osteoporosis 4 (17) 25 (19) 10 (13) 19 (26) Loss of height 5 (22) 11 (8) 6 (8) 10 (13) Height (inches) Lifetime steroid dose (g) * Acute rejection episodes Mean no. of rejection episodes * Patients with rejection 10 (43) 50 (38) 21 (27) 39 (53) Fracture 5 (6) 18 (24) NOTE. Values expressed as mean SD or number (percent). *P.01 P.001 P.05 Figure 1. Percentage of change in BMD was greatest from pretransplantation to 6 months posttransplantation ( g/cm 2 pretransplantation v g/cm 2 at 6 months). The rate of change during this period was 4.2% (P.006). BMD was similar between patients with and without fracture up to 4 years after transplantation (P not significant). mon in patients with osteoporosis (P.08). After transplantation, no identifiable risk factors at 6 months, 1 year, or 2 years posttransplantation were associated with osteoporosis. When risk factors for bone loss were compared among men and women, women had a greater incidence of PBC (P.001) and a lower incidence of alcohol hepatitis (P.001) and viral hepatitis (P.04). Women were more likely to have a family history of osteoporosis (P.04), whereas men were more likely to smoke cigarettes (P.01). Women were more likely to have acute rejection episodes (P.005) and were administered a greater dose of cumulative steroids (P.01) compared with men. BMD remained statistically lower in female liver transplant recipients until 4 years after transplantation (Fig. 3). Multivariate analysis of female patients alone reported no correlation of risk factors for fracture. All power calculations were made using power of 80% and of 0.05, assuming independent samples using observed means and variances. With the given

5 Bone Density Following Liver Transplantation 861 Figure 2. Percentage of patients with osteopenia (defined as a T score < 1.0) pretransplantation was 50% and increased to 63% at 6 months posttransplantation. By 1 year posttransplantation, the percentage of patients with osteopenia was similar to pretransplantation (54%). Likewise, percentages of patients with osteoporosis (defined as a T score < 2.5) were 17% pretransplantation, 28% at 6 months posttransplantation, and 16% at 1 year posttransplantation. sample, we could show differences of 0.88 in pretransplantation DEXA, 1.12 in 6-month posttransplantation DEXA, and 0.91 in the change from pretransplantation to 6-month posttransplantation DEXA between the fracture and no-fracture groups. A study powered to test for differences, assuming similar proportions of fracture and no-fracture patients, would require more than 1,000 patients for pretransplantation DEXA, 1,000 patients for 6-month posttransplantation DEXA, and 10,000 patients for the change from pretransplantation to 6-month posttransplantation DEXA. months posttransplantation (3% to 7%). Our study is consistent with these results, reporting a 4% loss in bone density during the first 6 months post liver transplantation. Low BMD has been proven to be a risk factor associated with fractures in postmenopausal asymptomatic women. DEXA is considered the gold standard for monitoring bone loss in these patients. 20,21 Furthermore, in this subgroup, BMD at the axial skeleton has been shown to correlate well with BMD at the appendicular skeleton. 22 Association of low bone mass and fracture is yet to be proven in liver transplant recipients. In agreement with Leidig-Bruckner et al, 10 we found that DEXA did not predict fracture in liver transplant recipients. Conversely, other studies have shown that BMD correlates with fracture. 3,12,14 Likewise, there is little agreement in the literature with regard to predictors of fracture in liver transplant recipients. In accordance with previously reported data, our data show that patients with alcoholic liver disease were less likely to have osteoporosis and patients with PBC were more likely to experience bone loss. 1,8,13,23 In our study, we report a significantly greater incidence of fractures in female liver transplant recipients compared with male transplant recipients. Female patients were more likely to be shorter, have PBC, have a family history of osteoporosis, experience acute rejection episodes, and be administered greater cumulative doses of steroids. All these characteristics are risk factors for bone loss. It is possible that the cumulative influence of these risk factors makes women more prone to fracture after transplantation. However, it also is possible, and our data suggest likely, that female sex is the greatest risk factor for fractures. This possibility is supported because no risk factors for fracture were found in male Discussion We report the largest series of liver transplant recipients followed up for bone loss to date. Previous reports have ranged from 12 to 91 liver transplant recipients. 1-3,6,9-17 Our reported prevalence of fracture (15%) was at the lower range of previously reported data. Previous studies reported up to a 50% prevalence of fractures by using serial radiography to determine fracture rates. Serial radiographic evidence of fracture was not monitored in this study; rather, radiography was performed when patients identified symptoms suggesting fracture. Early posttransplantation monitoring of bone mineral loss is well documented in the literature. 1,14,17-19 These studies have shown rapid bone loss in the first Figure 3. BMD was lower pretransplantation and remained statistically significantly lower in female compared with male transplant recipients until 4 years after transplantation.

6 862 Hardinger et al patients. Furthermore, within the female subgroup in multivariate analysis, no risk factors for fracture were found. Other investigators have not analyzed results based on relationship with sex, raising questions about their conclusions. The association of corticosteroids and bone loss remains a controversial issue. Some reports associated bone loss after liver transplantation with steroids and rejection episodes, 14,23 whereas others did not report a correlation. 2,3,6,9,19 A recent study examined the effect of steroid withdrawal on bone density. In one arm of the study, prednisone dose was tapered (n 41) and compared with a control group that remained on steroid therapy (n 28). 23 BMD at the lumbar spine significantly increased in both groups at the end of the study period (mean follow up, 5 years), whereas z score was statistically significantly higher in the steroid-withdrawal group. Liver transplant recipients have lower BMD and are at increased risk for fracture. Serial measurements of BMD at the lumbar spine do not appear to predict fracture risk post liver transplantation; however, data suggest that female sex is the strongest predictor of fracture after liver transplantation. References 1. Meys E, Fontanges E, Fourcade N, Thomasson A, Pouyet M, Delmas PD. Bone loss after orthotopic liver transplantation. Am J Med 1994;97: Haagsma EB, Thijn CJ, Post JG, Slooff MJ, Gips CH. Bone disease after orthotopic liver transplantation. J Hepatol 1988;6: McDonald JA, Dunstan CR, Dilworth P, Sherben K, Shield G, Evans RA, et al. Bone loss after liver transplantation. Hepatology 1991;14: Porayko MK, Wiesner RH, Hay JE, Krom RA, Dickson ER, Beaver S, et al. Bone disease in liver transplant recipients: Incidence, timing, and risk factors. Transplant Proc 1991;23: Arnold JC, Hauser D, Ziegler R, Kommerell B, Otto G, Thielman L, et al. Bone disease after liver transplantation. Transplant Proc 1992;24: Navasa M, Monegal A, Guanabens N, Peris P, Rimola A, Munoz-Gomez J, et al. Bone fractures in liver transplant patients. Br J Rheumatol 1994;33: Diamond TH, Stiel D, Lunzer M, McDowall D, Eckstein RP, Posen S. Hepatic osteodystrophy. Static and dynamic bone histomorphometry and serum bone Gla-protein in 80 patients with chronic liver disease. Gastroenterology 1989;96: Bonkovsky HL, Hawkins M, Steinberg K, Hersh T, Galambos J, Henderson JM, et al. Prevalence and prediction of osteopenia in chronic liver disease. Hepatology 1990;12: Monegal A, Navasa M, Guanabens N, Peris P, Pons F, Martinez de Osaba MJ, et al. Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A. Calcif Tissue Int 2001;68: Leidig-Bruckner G, Hosch S, Dodidou P, Ritschel D, Conradt C, Klose C, et al. Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: A follow-up study. Lancet 2001;357: Trautwein C, Possienke M, Schlitt HJ, Boker KH, Horn R, Raab R, et al. Bone density and metabolism in patients with viral hepatitis and cholestatic liver diseases before and after liver transplantation. Am J Gastroenterol 2000;95: Crosbie OM, Freaney R, McKenna MJ, Curry MP, Hegarty JE. Predicting bone loss following orthotopic liver transplantation. Gut 1999;44: Giannini S, Nobile M, Ciuffreda M, Lemmolo RM, Dalle Carbonare L, Minicuci N, et al. Long-term persistence of low bone density in orthotopic liver transplantation. Osteoporos Int 2000; 11: Monegal A, Navasa M, Guanabens N, Peris P, Pons F, Martinez de Osaba MJ, et al. Bone disease after liver transplantation: A long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics. Osteoporos Int 2001;12: Hamburg SM, Piers DA, van den Berg AP, Slooff MJ, Haagsma EB. Bone mineral density in the long term after liver transplantation. Osteoporos Int 2000;11: World Health Organization Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report Series 843. Geneva: World Health Organization, Julian BA, Laskow DA, Dubovsky J, Dubovasky EV, Curtis JJ, Quarles LD. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991;328: Almond MK, Kwan JTC, Evans K, Cunningham J. Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 1994;66: Valero MA, Loinaz C, Larrodera L, Leon M, Moreno E, Hawkins F. Calcitonin and bisphosphonates treatment in bone loss after liver transplantation. Calcif Tissue Int 1995;57: Kanis JA, Melton LI, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res 1994;9: Lips P. Epidemiology and predictors of fractures associated with osteoporosis. Am J Med 1997;103(suppl):S3-S Grampp S, Genant HK, Mathur A, Lang P, Jergas M, Takada M, et al. Comparisons of noninvasive bone mineral measurements in assessing age-related loss, fracture discrimination, and diagnostic classification. J Bone Miner Res 1997;12: Mart G, Gomez R, Jodar E, Loinaz C, Moreno E, Hawkins E. Long-term follow-up of bone mass after orthotopic liver transplantation: Effect of steroid withdrawal from the immunosuppressive regimen. Osteoporos Int 2002;13: