Pilar Peris

Osteoporosis and bone mineral metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation.

Abstract. The purpose of this study was to determine the prevalence of osteoporosis, to estimate the bone turnover and hormonal status, and to identify the factors associated with bone disease in patients with end-stage liver disease who were referred for orthotopic liver transplantation.A prospective study was performed on 58 cirrhotic patients (6 with primary biliary cirrhosis, 14 with alcoholic cirrhosis, and 38 with posthepatitic cirrhosis), who were referred for orthotopic liver transplantation. Patients, excluding those with primary biliary cirrhosis, were classified in Child-Pugh groups according to the severity of liver disease (class B [28 patients], class C [24 patients]). Biochemical parameters of bone mineral metabolism and standard liver function tests were measured in all patients. Additionally, serum osteocalcin, urinary hydroxyproline/creatinine ratio, serum intact parathyroid hormone, serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, folliclestimulating hormone, and luteinizing hormone levels were determined in patients and controls within the same age range. Plasma testosterone, sex hormone-binding globulin levels, and free testosterone index were obtained for all men included in the study.Bone mass of the lumbar spine and femur were measured by dual X-ray absorptiometry (DPX-L), and were expressed as a standard deviation of mean values (Z-score) from a sex and age-matched control group. Spinal X-rays were obtained to assess vertebral fractures. Osteoporosis was considered as a factor in spinal bone mineral density with a Z-score below 2 or at least one vertebral fracture.Twenty-five patients (43%) had osteoporosis, with lower bone mass measurements in the lumbar spine than in the femoral neck (P < 0.005). Alcoholic and Child-Pugh C patients showed the lowest femoral bone mineral density values. Cirrhotic patients showed lower osteocalcin levels than controls (14.3 ± 5.9 vs. 18.2 ± 8.1 ng/ml; P < 0.05) and showed increased urinary hydroxyproline (125.1 ± 51.5 vs. 107.9 ± 26.6 nM/mg creatinine; P < 0.05). Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone levels were significantly lower in cirrhotic patients than in controls (10.3 ± 9.1 vs. 23.1 ± 26.6 ng/ml; P= 0.000), (12.9 ± 9.1 vs. 48.3 ± 11.5 pg/ml; P= 0.000), (16.6 ± 9.2 vs. 27.9 ± 8.2 pg/ml; P= 0.000), with no differences between Child-Pugh groups. Alcoholic Child-Pugh C patients showed the lowest 25-hydroxyvitamin D serum values (4.5 ± 2.2 ng/ml; P < 0.05). Male patients had lower testosterone levels than controls (302.5 ± 229.4 vs. 556.7 ± 146.5 ng/dl; P= 0.000), with increased sex hormone-binding globulin values. Levels of testosterone and gonadotropin were related to Child-Pugh classification. No correlation was found between bone mass and hormonal values.A significant decrease in bone mass, particularly in the lumbar spine, is seen in end-stage cirrhotic patients. Reduced bone formation and significant disorders of bone mineral metabolism, such as vitamin D deficiency, reduced parathyroid hormone levels, and hypogonadism are involved. Moreover, severity and etiology of the liver disease are the main risk factors for developing bone loss and mineral metabolism disorders in patients referred for orthotopic liver transplantation.

Bone Disease After Liver Transplantation: A Long-Term Prospective Study of Bone Mass Changes, Hormonal Status and Histomorphometric Characteristics

Abstract: After liver transplantation there is a high incidence of fractures, with important rates of bone loss during the first months. However, the long-term evolution of bone mass and metabolism parameters have been scarcely studied. In order to determine the incidence and risk factors involved in the development of skeletal fractures and to analyze the long-term evolution of bone mass, bone turnover and hormonal status after liver transplantation, a 3-year prospective study was performed in 45 patients following liver transplantation. Serum osteocalcin, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH D) and testosterone levels (men), and bone mass at the lumbar spine and femur were measured before and sequentially at different time points during 3 years. Spinal X-rays were obtained during the first year. Histomorphometric analysis of bone biopsies obtained in 24 patients within the first 12 hours after surgery and 6 months after transplantation was performed. Fifteen patients (33%) developed fractures after liver transplantation, and pre- transplant risk factors for fractures were age and low bone mass (odd”s ratio for osteoporosis, 95% confidence interval: 5.69, 1.32–24.53). Serum PTH, osteocalcin, 25-OH D, testosterone and creatinine levels increased after transplantation. Moreover, PTH correlated with creatinine and osteocalcin values. Bone mass decreased during the first 6 months and reached baseline values at the lumbar spine the second year, with posterior significant recovery at the femoral neck. Long term evolution of femoral neck BMD correlated with PTH levels. Six months after transplantation bone histomorphometric data showed an increase in bone formation parameters. After liver transplantation there is a high incidence of fractures, specially in elderly patients and those with osteoporosis. Bone mass decreased in the short-term period and improved, initially at the lumbar spine and later at the femur, according to histomorphometric evidences of an increase in bone formation. The increase in creatinine values induces a secondary hyperparathyroidism that influences the changes in femoral bone mass. Treatment of osteoporosis shortly after liver transplantation may be important in the prevention of bone fractures, particularly in patients with low bone mass.

Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A

The purpose of this study was to compare the effects of Cyclosporine A (CyA) and FK506 on bone mass and mineral metabolism in liver transplantation (LT) patients. A prospective study was performed on 18 male patients who underwent LT treated with CyA, and 7 LT patients who received FK506. Bone mineral density (BMD) of the lumbar spine and proximal femur (DPX-L) was measured before and at 6, 12, and 24 months after transplantation. Moreover, intact parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD) levels were determined at the same time. The cumulative dose of glucocorticoids was calculated in all patients. At 6 months, lumbar BMD decreased 5.2 ± 1.2 % (P=0.0005) and 2.9 ± 2.1 % (p=ns) in CyA and FK506 groups, respectively. Lumbar BMD reached baseline values at 1 year in the FK506 group and 2 years after LT in the CyA group. Moreover, significant intergroup differences in femoral neck BMD changes after 2 years of transplant were observed (CyA: −5.2 ± 1.97 versus FK506: +1.55 ± 2.2 %;P=0.039). In the first year posttransplant both groups showed a marked increase in PTH and 25OHD levels. The mean cumulative dose of glucocorticoids was higher in the CyA group (CyA group 11.06 ± 0.46 g versus FK 506 group 6.71 ± 0.42 g;P<0.001), and multiple linear regression analysis showed a negative correlation between BMD changes at the lumbar spine and mean cumulative dose of glucocorticoids (P=0.022). In conclusion, our data suggest that after liver transplantation treatment with FK506 shows a more favorable long-term effect on bone mass evolution than CyA therapy. These differences seem to be associated with the lower dose of glucocorticoids used in the FK506 group.

Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis.

OBJECTIVES:Osteopenia increases the morbidity of primary biliary cirrhosis (PBC). In this study, we have compared two bisphosphonates, alendronate and cyclical etidronate, that inhibit osteoclast-mediated bone resorption and have examined their effects on bone mass in patients with this disease.METHODS:A total of 32 women with PBC were randomly assigned to receive alendronate (10 mg/day) or etidronate (400 mg/day) for 14 days every 3 months. Bone mineral density of the lumbar spine and proximal femur were measured initially and every 6 months. Bone fractures and markers of bone mineral metabolism were also evaluated.RESULTS:Sixteen patients were allocated to each group, which were comparable with respect to the severity of PBC and osteopenia. Thirteen patients in each group completed the 2-yr trial. Both treatments increased bone mineral density after 2 yr, although the increase at the lumbar spine and at the proximal femur was significantly higher in patients receiving alendronate than in patients on etidronate. This higher effect of alendronate paralleled with changes in the biochemical markers of bone turnover. No patient developed new vertebral fractures, but new peripheral fractures were detected in two patients on alendronate and in one on etidronate. There were no serious adverse effects. Neither treatment impaired liver function or cholestasis.CONCLUSIONS:Alendronate effectively increases bone mass and has greater antiresorptive power than etidronate in patients with primary biliary cirrhosis, and is associated with minor or no side effects.

Etidronate versus fluoride for treatment of osteopenia in primary biliary cirrhosis : Preliminary results after 2 years

BACKGROUND & AIMS Because osteopenia increases morbidity of primary biliary cirrhosis (PBC), the effects of cyclical etidronate vs. sodium fluoride on bone mass were compared in patients with PBC. METHODS Thirty-two women with PBC were randomly assigned to receive etidronate (400 mg/day during 14 days every 3 months) or fluoride (50 mg/day, enteric-coated tablets). Bone mineral density of the lumbar spine and proximal femur were measured initially and every 6 months. Bone fractures were also evaluated. RESULTS Sixteen patients were allocated into each group, which were comparable with respect to the severity of PBC and osteopenia. Thirteen patients with etidronate and 10 patients with fluoride completed 2 years in the study. In the etidronate group, bone mineral density increased in the lumbar spine (P = 0.02) and did not change in the proximal femur. In the fluoride group, lumbar bone mineral density did not change but femoral bone mass decreased, particularly in the Wards triangle. Two patients in the fluoride and none in the etidronate group developed new vertebral fractures, and the number of new nonvertebral fractures was similar in both groups. Neither treatment impaired liver function or cholestasis. CONCLUSIONS Cyclical etidronate is more effective and better tolerated than sodium fluoride in preventing bone loss in PBC.

Collagen‐Related Markers of Bone Turnover Reflect the Severity of Liver Fibrosis in Patients with Primary Biliary Cirrhosis

The influence of a nonskeletal disease with increased connective tissue synthesis or degradation in the collagen‐related markers of bone turnover has been evaluated in 34 women with primary biliary cirrhosis (PBC; age range 41–81 years), a disease with increased hepatic fibrosis, often associated with osteoporosis. Serum osteocalcin (BGP), and carboxy‐terminal (PICP) and amino‐terminal (PINP) propeptides of type I collagen were assessed as indexes of bone formation, whereas serum tartrate‐resistant acid phosphatase (TRAP), and cross‐linked carboxy‐terminal telopeptide of type I collagen (ICTP), and urinary hydroxyproline (HYP), pyridinoline (PYR), deoxypyridinoline (DPYR), and type I collagen cross‐linked N‐ (NTX) and C‐telopeptide (CTX) were measured as markers of bone resorption. The histologic stage of the disease and serum amino‐terminal propeptide of type III collagen (PIIINP) as an index of liver fibrogenesis were also evaluated. BGP levels were significantly lower, whereas PICP and PINP levels were higher in patients than in controls. Among the bone resorption markers, serum ICTP and urinary PYR, DPYR, HYP, NTX, and CTX levels were significantly higher in patients than in controls. Serum PIIINP levels were also increased in PBC patients. BGP did not correlate with PICP and PINP, but these markers of bone formation as well as ICTP, PYR, DPYR, and NTX correlated with serum PIIINP levels. Serum TRAP did not correlate with collagen‐related markers of bone resorption. Moreover, patients with PIIINP and bilirubin above normal levels had higher PICP, PINP, ICTP PYR, DPYR, CTX, and NTX. These markers correlated with the histologic stage of the disease, but not with osteopenia measured by densitometric procedures in 22 patients. In conclusion, collagen‐related markers of bone turnover do not reflect bone remodeling in PBC. The close association of these markers with PIIINP and the clinical and histologic stage of the liver disease suggests that they are influenced by liver collagen metabolism.

Low Bone Mass and Severity of Cholestasis Affect Fracture Risk in Patients With Primary Biliary Cirrhosis

BACKGROUND & AIMS The influence of osteoporosis and liver disease on fracture risk is not well characterized in patients with primary biliary cirrhosis (PBC). We studied a large series of women with PBC to assess the prevalence and risk factors for fractures and the fracture threshold. METHODS In female patients with PBC (n = 185; age, 55.7 +/- 0.7 years; range 28-79 years), age, duration of PBC, menopausal status, and histologic stage and severity of liver disease were assessed. Vertebral and non-vertebral fractures were recorded in 170 and 172 patients, respectively. Osteoporosis and osteopenia were diagnosed based on densitometry analysis. RESULTS The prevalences of vertebral, non-vertebral, and overall fractures were 11.2%, 12.2%, 20.8%, respectively. Osteoporosis was significantly more frequent in patients with PBC than in normal women. Osteoporosis was associated with age, weight, height, histologic stage, severity, and duration of liver damage; fractures were associated with osteoporosis, menopause, age, and height but not with severity of PBC. Osteoporosis was a risk factor for vertebral fracture (odds ratio [OR], 8.48; 95% confidence interval [CI]: 2.67-26.95). Lumbar T score <-1.5 (OR, 8.27; 95% CI: 1.84-37.08) and femoral neck T score <-1.5 (OR, 6.83; 95% CI: 1.48-31.63) were significant risk factors for vertebral fractures. CONCLUSIONS Fractures, particularly vertebral fractures, are associated with osteoporosis, osteopenia, and T scores less than -1.5, whereas osteoporosis and osteopenia are associated with the severity of liver damage. Patients with T scores less than -1.5 might require additional monitoring and be considered for therapy to prevent fractures.

Usefulness of biochemical markers of bone turnover in assessing response to the treatment of paget’s disease

The aim of this study was to investigate the usefulness of biochemical markers of bone turnover for monitoring treatment efficacy of Pagets disease of bone, and also to evaluate the utility of biological variation data in choosing the best markers for assessment of biochemical response to therapy. Thirty-eight patients with Pagets disease were included in a prospective study. All received 400 mg/day of oral tiludronate for 3 months. In 31 patients that completed treatment, biochemical markers were measured at baseline and at 1 and 6 months after treatment ended. In serum we determined the levels of total alkaline phosphatase (tAP), bone alkaline phosphatase (bAP), procollagen type I N-terminal propeptide (PINP), and C-terminal telopeptide of type I collagen (sCTx). Urine samples were analyzed for hydroxyproline (Hyp) and for C- and N-terminal telopeptides of type I collagen (CTx and NTx, respectively). Quantitative bone scintigraphy was performed at baseline and at 6 months after discontinuation of therapy. A ratio for monitoring response to treatment was obtained for each marker. This ratio reflected the size of treatment response of the marker in relation to the value of its critical difference. Thus, ratio values of >1 indicated a significant decrease of the marker after therapy. In addition, response to therapy was evaluated according to disease activity. Mean values of all markers of bone turnover decreased significantly after therapy. Serum bAP and PINP and urinary NTx showed the highest percentage reduction (between 58% and 68%). Furthermore, serum bAP and PINP showed the highest ratios for monitoring changes induced by treatment, followed by serum tAP and urinary NTx. sCTx and urinary CTx as well as Hyp showed mean ratios for monitoring changes of <1, indicating a low sensitivity for monitoring treatment. Patients with polyostotic disease showed a continuous decrease in mean values for all markers at 6 months from the end of therapy, whereas, in monostotic patients, there was a trend toward increased levels at this timepoint. In conclusion, serum bAP and PINP were the most sensitive markers for monitoring treatment efficacy in Pagets disease, although serum tAP and urinary NTx were also sensitive markers for monitoring changes. Data on biological variation are useful for assessing actual changes induced by treatment.

Septic arthritis in heroin addicts

Over a 6-year period (1982 to 1988), 36 episodes of septic arthritis were diagnosed in 35 heroin addicts from Barcelona, Spain. Thirty (86%) were men and five (14%) were women, with a mean age of 24 years (range, 14 to 39). Twenty-nine episodes (80%) were monoarticular and seven (20%) were oligoarticular. The sacroiliac (16 cases), sternoclavicular (8), hip (5), and shoulder (4) joints were most frequently infected. Staphylococcus aureus and Pseudomonas aeruginosa were the etiological agents in 75% and 11% of episodes, respectively. Response to antibiotic treatment was good in 32 cases (90%), eight patients needed surgical drainage, and none died. We conclude that septic arthritis in heroin addicts localizes predominantly in axial joints. In our geographic area, infection with S aureus is more frequent than with gram-negative rods such as P aeruginosa or Serratia marcescens, which are most frequently found in reports from the United States.

Vertebral fractures and osteopenia in chronic alcoholic patients

To assess whether vertebral fractures are associated with osteopenia in chronic alcoholic patients, a transversal study was carried out in 76 chronic alcoholic males and 62 age-matched healthy males. Lumbar bone mineral density (BMD) by dual photon absorptiometry and spinal chest X-ray films were done in all patients. Twenty-seven patients (36%) had vertebral fractures, but only 5 of them had a BMD below the fracture threshold. Twenty-two patients (29%) had osteoporosis by densitometric criteria. There were no significant differences in lumbar BMD between alcoholic patients with and without vertebral fractures (1.11±0.2 versus 1.13±0.2, P=ns). Previous trauma was recorded in 24 of the 27 patients with vertebral fractures and in 28 of the 49 patients without vertebral fractures (P<0.001). Moreover, patients with vertebral fractures had more peripheral fractures than patients without vertebral fractures (81% versus 49%, P=0.01). Only one patient was aware of a previous episode of traumatic vertebral fracture. In conclusion, chronic alcoholics frequently have traumas and vertebral fractures, the latter despite having a lumbar BMD above the fracture threshold, suggesting a frequent but unrecognized association between both processes. These results suggest that both spine films and BMD measurements should be obtained for diagnosis of osteoporosis in alcoholic patients.