J. Muñoz-Gómez

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.

Significant loss of bone mass in patients with early, active ankylosing spondylitis : A followup study

OBJECTIVE To analyze whether inflammatory disease activity plays a substantial role in the loss of bone mass observed in ankylosing spondylitis (AS) patients who have not yet developed ankylosis. METHODS A longitudinal cohort study of 34 patients with early AS (duration <10 years) without ankylosis was conducted. The mean followup was 19 months. Loss of bone mass in defined regions of the lumbar spine and femoral neck was analyzed by dual x-ray absorptiometry. Patients were grouped according to biologic parameters of disease activity (erythrocyte sedimentation rate or C-reactive protein level). Group 1 consisted of 14 patients with active disease; group 2 comprised 20 patients with inactive disease. Serum levels of interleukin-6 (IL-6) and of hormones (sex, thyroid, and calciotropic), vertebral mobility (Schober test), daily physical activity, and treatment administered were recorded every 6 months for all patients. RESULTS At the end of the followup period, patients with active AS showed a significant reduction in bone mass in the lumbar spine (mean 1.01 gm/cm2 at study entry versus 0.961 gm/cm2 at followup [P = 0.005]) and femoral neck (0.849 gm/cm2 versus 0.821 gm/cm2 [P = 0.015]), which represented losses of 5% and 3%, respectively. In contrast, no significant reduction in bone mass was observed in patients with inactive AS. As expected, serum IL-6 levels were significantly higher in patients with active AS than in those with inactive disease (mean +/- SD 8.3 +/- 9 pg/ml versus 2.8 +/- 5 pg/ml [P = 0.008]). No significant differences were observed between the 2 groups in any of the other variables analyzed. CONCLUSION The observation that loss of bone mass in AS occurred only in patients with persistent active disease strongly suggests that inflammatory activity of the disease itself plays a major role in the pathophysiology of the early bone mineral disorders observed in these patients.

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.

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.

Biochemical markers of bone turnover after surgical menopause and hormone replacement therapy

The objective of this study was to evaluate the effect of surgical menopause and hormone replacement therapy (HRT) on the new biochemical markers of bone turnover. Fourteen women who had undergone surgical menopause and began HRT 3 months after surgery were recruited for a 1-year study. Results were compared with a control group of 31 healthy premenopausal women of similar age. Serum samples were obtained to determine total alkaline phosphatase, bone alkaline phosphatase, propeptides carboxy- and amino-terminal of type I procollagen (PICP, PINP), osteocalcin, tartrate-resistant acid phosphatase, and carboxy-terminal telopeptides of type I collagen (ICTP and serum CTX). Urine samples were analyzed for hydroxyproline, pyridinoline, deoxypyridinoline, alpha- and beta-carboxy-terminal telopeptides of type I collagen (alpha-CTX and beta-CTX), and amino-terminal telopeptide of type I collagen (NTX). Determinations were performed after 3 months of surgical menopause and after 3 and 9 months of HRT. All biochemical markers increased after menopause, and most of them normalized after 9 months of HRT. Serum PINP showed the highest proportion of increased values after surgery among bone formation markers (62%), as well as the highest mean percent increase (101%). Among bone resorption markers in postmenopausal women, urinary beta-CTX, alpha-CTX, NTX, and serum CTX showed the highest proportion of increased values (100%, 67%, 58%, 58%, respectively) as well as the greatest mean percent increase. They were also the markers with the most marked response to HRT. In conclusion, serum PINP is the most sensitive marker of bone formation, whereas beta-CTX is the most sensitive marker of bone resorption after surgical menopause. In addition, both markers showed the highest response after HRT.

Systemic involvement of dialysis-amyloidosis

A new type of amyloidosis, predominantly osteoarticular, has recently been recognized in uremic patients on hemodialysis, beta 2-microglobulin being the major constituent protein. Nowadays, it is not clear whether the amyloid deposition is limited to osteoarticular structures or whether it has a systemic character. In order to investigate the extension of dialysis amyloidosis, we studied 26 patients receiving hemodialysis treatment (mean time 12.2 years) for chronic renal failure due to nonamyloid nephropathy and who were affected by symptomatic dialysis amyloidosis. Twenty-two patients developed a carpal tunnel syndrome, and amyloid arthropathy was present in 21. Subcutaneous abdominal fat aspiration, rectal and skin biopsy, and two-dimensional echocardiography were performed in most of the patients, searching for the visceral involvement. Surgical pieces (one stomach and two colon) and three necropsies of symptomatic patients were included in the systemic investigation. Also, we studied five necropsies of patients without articular symptoms. Histological confirmation of amyloid visceral involvement was demonstrated in 15 (58%) of the 26 patients studied. When positive two-dimensional echocardiograms were included, the percentage increased to 81%. No differences in the rate of visceral involvement could be found between the two clinical groups (with and without carpal tunnel syndrome). Two-dimensional echocardiography represents the most useful tool to search for the visceral involvement of beta 2-microglobulin amyloidosis, followed by abdominal fat aspiration and rectal biopsy. Amyloid deposits were resistant to potassium permanganate treatment and reacted with antihuman beta 2-microglobulin (avidin-biotin-peroxidase method).

The clinical significance of amyloid fat deposits in rheumatoid arthritis: A systematic long-term followup study using abdominal fat aspiration

OBJECTIVE To analyze the prevalence of subclinical amyloid fat deposits in patients with rheumatoid arthritis (RA) and to evaluate its clinical significance. METHODS A cohort of 313 adult RA patients were included in this prospective observational study. Systematic abdominal subcutaneous fat aspiration (ASFA) was performed on all patients at study entry. The prevalence of visceral amyloidosis at study entry and at the end of followup was analyzed for patients with a positive ASFA test result. Followup ranged from 1 to 14 years (mean +/- SD 6.7 +/- 4.1 years). Patients with clinical and subclinical amyloidosis were compared with regard to clinical characteristics and the degree of amyloid deposits in abdominal fat. RESULTS The first ASFA test found amyloid in the abdominal fat of 51 patients (16.3%), and subsequent ASFA tests found amyloid in the abdominal fat of 10 additional patients. At the time of the ASFA test, amyloidosis was subclinical in 45 of these 61 patients, 41 of whom were followed up. During followup, 11 of these 41 patients developed renal involvement, 5 due to amyloid nephropathy. Thus, amyloidosis remained subclinical in at least 30 of 41 patients (73%) throughout followup. Marked amyloid fat deposits were found more frequently in patients with clinical amyloidosis than in those whose amyloidosis remained subclinical at the end of followup (57% versus 22%; P = 0.04). CONCLUSION Amyloid fat deposits are not uncommon in adult RA. In the majority of patients, the deposits do not indicate clinically evident organic dysfunction, even after several years of followup. Patients with more extensive fat deposits may have a higher risk of developing clinical amyloidosis.