Bone mineral density, biochemical markers and skeletal fractures in haemodialysis patients

Pablo Uren a 0 2 3 4 Oana Bernard-Poenaru 1 2 Agn e`s Ostertag 0 2 Claude Baudoin 0 2 Martine Cohen-Solal 0 2 Tom Cantor 2 5 Marie Christine de Vernejoul 0 2 0 INSERM Unite 349 , Ho pital Lariboisie` re, Paris, France 1 Service Central de Biophysique, Laboratoire de Biologie Endocrinienne , Ho pital Lariboisie` re, Paris, France 2 Vernejoul, INSERM Unit e 349 , H opital Lariboisi e`re, 2, rue 3 Service de Ne phrologie-Dialyse , Clinique de l'Orangerie, Aubervilliers, France 4 Service de Physiologie et Explorations Fonctionnelles , Ho pital Bichat, Paris, France 5 Scantibodies Laboratory , Inc., Santee, CA, USA Background. End-stage renal disease is often associated with altered bone metabolism. Methods. In order to investigate the determinant factors of bone mineral density (BMD) and the risk factors of fractures, we studied 70 patients; 26 women (23 post-menopausal) and 44 men, (meanSD) aged 60.514.3 years, treated by standard haemodialysis (HD) for 6.46.8 years. Main circulating bone biochemical markers were assessed and BMD was measured with a Lunar DPX densitometer at five sites. BMD results are expressed as a function of age and gender (Z-score). Results. Mean Z-score was markedly decreased at the mid-radius ( 2.751.23) whereas it was normal at the femoral neck ( 0.421.13) and lumbar spine (0.022.13), and total body ( 0.621.53). Time on HD was negatively correlated to the Z-score at the mid-radius and total body but not at the other sites. Serum intact parathyroid hormone (iPTH), whole PTH or cyclase activating PTH (CAP) and bonespecific alkaline phosphatase concentrations were negatively correlated with Z-scores at all sites. Twenty-one out of 70 patients had sustained a total of 27 fractures since the beginning of dialysis therapy (seven ribs, seven ankles, six vertebrae, three humerus, two wrists and two hips). They had a total body Z-score significantly lower than that of patients without fractures, 1.341.54 vs 0.371.46, respectively (P<0.031); however, their Z-scores at the other sites were not different. They were on HD for longer time, 10.49.5 vs 5.05.1, respectively (P<0.003), and the relative risk of skeletal fractures was 6.4 times greater after 10 years of HD. The seven patients with rib fractures had a decreased Z-score at most of the sites but not at the mid-radius. Rib fractures but no other fractures were associated with markedly decreased body weight, fat mass and serum leptin levels. Conclusions. In conclusion, the Z-score at the midradius was decreased in HD patients and correlated with high serum PTH but not with fractures. Bone fractures were associated with the time passed on HD and with a low total body Z-score. Rib fractures were frequent and associated with a poor nutritional state. Introduction Chronic renal failure is often associated with alterations in calcium and phosphate metabolism. Once haemodialysis (HD) has begun, bone histological signs of secondary hyperparathyroidism can be found in >50% of the patients. However, clinical evidence of low bone turnover or adynamic bone disease can be seen in as many as one-third of these patients. Other less frequent bone diseases such as osteomalacia, aluminum-related bone disease, fluorosis, strontium overload or mixed bone diseases can be observed in the rest of the patients [1]. In addition, because of their advanced age, post-menopausal status in women, sedentary lifestyle, nutritional state, history of prior renal transplantation and treatment including steroids, these patients may also be expected to be at high risk for developing osteoporosis [2]. These different manifestations of the renal osteodystrophy can roughly be suspected on the basis of Subjects and methods Patients Seventy adult uraemic patients, all Caucasian, 26 females and 44 males (23 out of the 26 women were post-menopausal), on maintenance HD were included into the present crosssectional study after their informed consent. All the patients were treated in the dialysis centre of the Clinique de lOrangerie. Their mean (SD) age was 60.514.3 years (range 2187 years). Mean duration of HD treatment was 6.46.8 years. All the patients were treated by conventional HD 45 h, three times a week, using hollow fibre dialysers, either hemophane (GFS-20, Gambro) or cellulosic (TCA 170, Baxter), against a dialysis bath containing 3236 mmol/l of bicarbonate, 0.85 mmol/l of magnesium, 1.50 (nine patients) to 1.75 mmol/l of calcium, and 23 mmol/l of potassium. The mean Kt/V for the group of patients was 1.470.27. Their residual creatinine clearance was <3 ml/min and all patients were oligo-anuric ( 200 ml/24 h). Underlying nephropathy types were: six nephrosclerosis, eight interstitial nephropathy, nine polycystic kidney disease, 16 chronic glomerulonephritis, six congenital nephropathy, 10 diabetic nephropathy, one tuberculosis and 14 of unknown etiology. At the moment of the evaluation none of the patients, in particular the post-menopausal women, was receiving or had received within the 12 months previous Pre-dialysis blood sampling was performed after a 12-h fast. Plasma calcium was determined using atomic absorption spectrometry, plasma phosphorus using a Technicon Auto Analyzer. Plasma iPTH was measured using a commercial radioimmunometric assay for intact human PTH 1-84 (Allegro Intact PTH, Nichols Institute, San Juan Capistrano, CA). This iPTH assay detects both 1-84 PTH and probably the described PTH inhibitor 7-84 PTH fragment [12]. The range of normal values was between 10 and 70 pg/ml. Plasma whole PTH (wPTH or CAP) was measured using a commercial radioimmunometric assay for whole human PTH 1-84 (Scantibodies Laboratories, CA) without any cross-reactivity with 7-84 PTH [13]. Normal values range from 5 to 50 pg/ml. Cyclase inactive PTH (CIP) was obtained by subtracting wPTH from iPTH and reflects the inhibitory action of PTH [3,12]. Plasma total alkaline phosphatase, albumin, 2-microglobulin and pre-albumin were measured by a routine clinical chemistry automated method. Plasma bAP was measured using a radioimmunometric assay (Tandem-R, Ostase) provided by Hybritech Europe S.A., Belgium. The mean SD value obtained in normal adult individuals was 11.84.3 ng/ml (normal range 4.025.0 ng/ml). Plasma vitamin D and 1,25(OH)2D3 were measured by radiocompetition assays as described previously [14,15]. Normal values for plasma vitamin D were 1040 ng/ml and for 1,25(OH)2D3, 2060 pg/ml. Serum cross-laps levels were measured using an ELISA from Osteometer, Biotech, Denmark. Normal values were 1.740.74 nmol/l in pre-menopausal women and 3.011.55 nmol/l in postmenopausal women. Serum leptin levels were measured using a radioimmunoassay, Linco kit, San Charles, MO. Normal values, in normal adult subjects with a body mass index between 18 and 25, were for women 3.711.1 ng/ml and for men 2.05.6 ng/ml. Age (years) 60.5 14.3 21.087.0 Ratio female/male 26/44 Duration of HD (years) 6.4 6.8 0.229.3 Total body weight (kg) 62.7 13.5 36.095.0 (...truncated)