Evaluation of bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hemodialysis patients.

UNLABELLED: Hemodialyzed patients have decreased bone strength not completely characterized. We evaluated bone microarchitecture in hemodialysis patients and compared it to that of subjects without renal disease by high-resolution peripheral quantitative computed tomography (HR-pQCT). Hemodialysis patients have a marked decreased in cortical density, thickness, and area with significant reduction in trabecular parameters that correlated with the severity of secondary hyperparathyroidism only in women. INTRODUCTION: Although fracture risk is greatly increased in dialysis patients, the corresponding decreased in bone strength has not been completely characterized. METHODS: We evaluated volumetric bone mineral density (vBMD) and bone microstructure by HR-pQCT at the distal radius and tibia in 50 hemodialyzed (HD) patients (30 females, mean age 53.2 ± 6 years and 20 males, mean age 59.1 ± 11 years) and 50 sex- and age-matched controls. RESULTS: At the distal radius HD, women showed a 29% reduction in total and trabecular density and trabecular bone volume fraction (p < 0.0001) compared to controls. Trabecular number was reduced by 25% (p < 0.0001), while trabecular separation was increased by 51%. Cortical thickness (-40%, p < 0.0001) and cortical area (-42%, p < 0.0001) were the parameters most reduced, while compact density was the parameter least reduced (-15%, p < 0.0001). Similar findings were found at the tibia. In HD men, HR-pQCT at the distal radius and tibia showed a reduction in volumetric density and microstructure parameters to a lesser extent than in women. In the hemodialyzed group, cortical thickness at the radius was negatively correlated with age both in women and men. At the distal radius and tibia, we found significant negative correlations between Log iPTH and total alkaline phosphatase with cortical vBMD(r = -0.48, p < 0.01; r = -0.69, p < 0.001), thickness (-0.37, p < 0.05; r = -0.60, p < 0.001), and area ((r = -0.43, p = 0.02; r = -0.65, p < 0.001) but only in women. CONCLUSION: We conclude that hemodialysis patients have a marked decreased in cortical density, thickness, and area with significant reduction in trabecular parameters that correlated with the severity of secondary hyperparathyroidism only in women.

DNA sequences downstream from the vitamin D response element of the rat osteocalcin gene are required for ligand-dependent transactivation.

The sequences in the rat osteocalcin gene that lie 3' to the vitamin D response element (VDRE) have been shown to augment transcriptional activation by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. These DNA sequences, however, are unable to bind the VDR or mediate 1,25-(OH)2D3 responsiveness independently of the VDRE. To further characterize this region, the functional properties of a series of mutant oligonucleotides were examined in transiently transfected ROS 17/2.8 cells. When these mutant oligonucleotides were expressed upstream of the heterologous herpes simplex virus thymidine kinase promoter, the bases between -420 and -414 of the rat osteocalcin gene were identified as critical for maximal transactivation by 1,25-(OH)2D3. Furthermore, mutation of these sequences in the context of the native osteocalcin promoter and enhancer totally abolished the ability of the VDRE to mediate 1,25-(OH)2D3 responsiveness. These bases, which are essential for the 1,25-(OH)2D3 responsiveness of the rat osteocalcin gene, are also present in a similar position, relative to the VDRE, in the human osteocalcin gene. To explore whether these sequences could enhance transactivation by other inducible transcription factors, they were examined for their ability to synergize with the chick vitellogenin estrogen response element and the rat somatostatin cAMP response element. When placed upstream to the herpes simplex virus thymidine kinase promoter and transfected into ROS 17/2.8 cells, these sequences were able to enhance transcriptional responsiveness to 17beta-estradiol and forskolin, respectively, demonstrating that they also contribute to transactivation by other inducible transcription factors.

Evaluation of cortical bone by peripheral quantitative computed tomography in renal transplant recipients.

BACKGROUND: The absolute risk of fractures in renal transplant patients is 3 times that of matched controls. Most of the symptomatic fractures are peripheral, suggesting a greater compromise of cortical bone. Peripheral quantitative computed tomography (pQCT) is a new imaging technique that allows separate noninvasive evaluations of cortical and trabecular bones. We investigated cortical bone by pQCT in 12 renal transplant patients (seven men and five women) for comparison with 27 normal controls. METHODS: pQCT (XCT 960, Stratec, Pforheim, Germany) was performed upon the distal radius of the nondominant forearm (15% the length of the ulna, proximal from the radius end plate). We evaluated total and cortical bone mineral density (TBMD, cBMD), total (cross-sectional) and cortical area (TA, cA), cortical thickness (cThk), endosteal and periosteal circumferences, and the buckling ratio (r/cThK). RESULTS: Compared with normal controls transplant patients as a whole showed a significant increase in TA, in endosteal circumference (P < .001), and in the buckling ratio (P < .001) with a significant reduction in cThK (P < .001). Female patients had a marked decrease in cA (51.4 vs 69.3 [pixel n]; P < .0001) and cThK (2.08 vs 2.78 mm; P < .0001). Male patients also had a decrease in cThK (2.54 vs 3.30 mm; P = .0001) and an increase in endosteal perimeter (31.2 vs 26.4 mm; P < .0001). Total time on dialysis prior to renal graft correlated negatively with cortical thickness (r = .62; P < .01). CONCLUSIONS: Our results suggest that a marked thinning of cortical bone may explain the increased incidence of peripheral fractures among renal transplant patients.

[Relationship between weight, body composition and bone mass in peritoneal dialysis]. / Relación entre peso, composición corporal y masa osea en diálisis peritoneal.

Patients in chronic dialysis show a decrease in total bone mass. The factors that determine this decrease are not well known. In normal populations weight and its compartments are important determinants of bone mass. We studied total bone mineral content (TBMC), a measure of bone mass, and body composition using DEXA densitometry in 65 patients (45 females and 20 males) who had been in peritoneal dialysis for a mean of 40.3 +/- 23.2 months. Forty-eight patients (73.8%) had been previously in hemodialysis. The mean total time in dialysis for these patients was 76.8 months. As a group patients showed a very significant positive correlation between TBMC and weight, height, and lean body mass. A negative correlation was found between TBMC with the time in dialysis and iPTH. In men we found significant simple positive correlations between TBMC and weight, height and lean body mass. In women we found simple positive correlations of TBMC with weight, height and lean body mass and a negative correlation with iPTH. In the multiple regression analysis, lean body mass was the only body composition parameter that had a significantly positive correlation with TBMC in men; in women only height correlated positively with TBMC and iPTH continued to correlate negatively with bone mass. When we considered pre and postmenopausal women separately, bone mass was correlated positively with height and lean body mass and negatively with iPTH in postmenopausal women and only with height in pre-menopausal females. We conclude that the lean body mass compartment. is the most important component of weight that determines TBMC in peritoneal dialysis patients particularly in males and postmenopausal women. In postmenopausal women, secondary hyperparathyroidism seems to be particularly detrimental on bone mass.

Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis.

Treatment with teriparatide (rDNA origin) injection [teriparatide, recombinant human parathyroid hormone (1-34) [rhPTH(1-34)]] reduces the risk of vertebral and nonvertebral fragility fractures and increases cancellous bone mineral density in postmenopausal women with osteoporosis, but its effects on cortical bone are less well established. This cross-sectional study assessed parameters of cortical bone quality by peripheral quantitative computed tomography (pQCT) in the nondominant distal radius of 101 postmenopausal women with osteoporosis who were randomly allocated to once-daily, self-administered subcutaneous injections of placebo (n = 35) or teriparatide 20 microg (n = 38) or 40 microg (n = 28). We obtained measurements of moments of inertia, bone circumferences, bone mineral content, and bone area after a median of 18 months of treatment. The results were adjusted for age, height, and weight. Compared with placebo, patients treated with teriparatide 40 microg had significantly higher total bone mineral content, total and cortical bone areas, periosteal and endocortical circumferences, and axial and polar cross-sectional moments of inertia. Total bone mineral content, total and cortical bone areas, periosteal circumference, and polar cross-sectional moment of inertia were also significantly higher in the patients treated with teriparatide 20 microg compared with placebo. There were no differences in total bone mineral density, cortical thickness, cortical bone mineral density, or cortical bone mineral content among groups. In summary, once-daily administration of teriparatide induced beneficial changes in the structural architecture of the distal radial diaphysis consistent with increased mechanical strength without adverse effects on total bone mineral density or cortical bone mineral content.

[Whole PTH and 1-84/84 PTH ratio for the non invasive determination of low bone turnover in renal osteodysthrophy]. / Utilidad de la determinación de PTH entera y del cociente PTH 1-84/7-84 en el diagnóstico no invasivo de osteodistrofia de bajo recambio.

The conventional intact PTH assays detect not only PTH 1-84 but also inactive fragments (as PTH 7-84) that accumulate in renal failure. There has been a recent development of a new PTH assay that measures only true 1-84 PTH (Whole PTH or CAP assay, Scantibodies). As 7-84 PTH fragment is antagonistic on bone effects of 1-84 PTH, Moniere-Faugere has suggested that 1-84/7-84 PTH ratio less than 1 is predictive of low turnover. We evaluated the usefulness of CAP assay and the 1-84/7-84 PTH ratio as markers of bone turnover in a groups of 24 patients in peritoneal dialysis (PD). Patients were classified as having low bone turn over if they had a Total PTH (similar to intact PTH) of less than 100 pg/ml. We also measured serum CrossLaps (CTX) as another serum resorption marker. Patients had a mean Whole PTH of 95.5 pg/ml and a mesan total PTH of 155.4 pg/l (range 9 to 900). Whole PTH represented 69.1% of total PTH. Fifteen patients (62.5%) had a total PTH of less than 100. These patients had a 1-84/7-84 relationship of 1.9 +/- 1.8 while 9 patients with Total PTH more than 100 had a relationship of 1.29 +/- 0.6 (p = NS). There was a tight correlation between Whole PTH and total PTH (r = 0.98; p < 0.0001) and with serum CTX (r = 0.78; p < 0.0001). We conclude that 1-84/7-84 ratio does not seem useful in the prediction of low bone turnover and that Whole PTH does not seem to be more useful than intact PTH in the prediction of bone turnover in this population. Future studies should correlate this markers with direct measurements of bone turnover in bone biopsies to demonstrate their usefulness in the prediction of the type of renal osteodystrophy.

[Urinary excretion of sodium and magnesium in idiopathic hypercalciuria]. / Excreción urinaria de sodio y magnesio en la hipercalciuria idiopática.

We have studied urinary sodium and magnesium excretion in 30 normal subjects (15 women and 15 men, mean age 43 +/- 14 years, mean weight 74 +/- 18 Kg) and in 60 hypercalciuric stone-forming patients, 30 with renal hypercalciuria (HR) (15 women and 15 men, mean age 39 +/- 10 years, mean weight 71 +/- 16 Kg) and 30 with absorptive hypercalciuria (HA), (15 women and 15 men, mean age 41 +/- 13 years, mean weight 69 +/- 12 Kg). The diagnosis of hypercalciuria and the classification in HA and HR was made with our ambulatory study protocol. Hypercalciuria was defined by a daily calcium excretion above 300 mg (men) or 220 mg (women), and patients with fasting calcium to creatinine ratio, and calcium per 100 ml of glomerular filtrate average value above 0.11 were considered to have HR. Control subjects and hypercalciuric patients were maintained on a diet containing 1200 mg Ca, 800 mg P, 200 mg Mg and 100 mmol Na per day for a 7-day period. Two 24-hour urine samples were collected on days 6 and 7 of this diet. On the morning of day 8, following a 12-hour fast, 300 ml of distilled water was drunk and a 2-hour urine sample was collected. A blood sample was taken halfway this time. In all blood and urine samples, calcium, magnesium, sodium, phosphorus and creatinine were quantified. Creatinine clearance and calcium, sodium and magnesium per 100 ml of glomerular filtrate were calculated from these determinations.(ABSTRACT TRUNCATED AT 250 WORDS)

[In vivo measurement of the mineral content of renal calculi by dual-photon absorptiometry. Correlation with its fragility to extracorporeal shockwave lithotripsy]. / Medición vivo del contenido mineral de los cáculos renales por densitometría de doble haz correlación con su fragilidad a la litotricia extracorpórea por ondas de choque.

After a few years of experience with extracorporeal shock wave lithotripsy (ESWL) and other fragmentation techniques, it has become apparent that stone fragility is a significant clinical distinction that should be taken into consideration when selecting a treatment program. In 30 unselected patients, stone mineral content, density and area were measured in vivo by dual-photon absorptiometry prior to perform ESWL treatment. Stone area determinations showed a median of 4.21 with a range of 0.46 to 49.7 cm2. Stone mineral content (g) and stone density (g/cm2) values were 2.47 and 0.46 with ranges of 0.37 to 13.7 and 0.167 to 1.203 respectively. The number of shocks needed for total fragmentation were 2375 with a range of 1200 to 7800. No correlation could be found between the number of shocks needed for fragmentation and the stone area or density. On the other hand, a strong linear correlation (r = 0.81, p < 0.001) (Fig. 1) could be demonstrated between stone mineral content and the number of shocks needed for fragmentation. Our results support the concept that size alone is not always a suitable criterion for selecting a stone as appropiate for ESWL, since no correlation could be found between stone area and the number of shocks needed for total fragmentation. We were also unable to find any correlation between in vivo stone density measured by dual-photon absorptiometry and the number of shocks required for stone fragmentation. Instead, a strong linear correlation between stone mineral content and its resistance to shock wave fragmentation was found. Therefore, calculation of mineral content appears to be the determinant of the amount of energy required for total fragmentation. Our results strongly suggest that in vivo stone mineral content measurement provides helpful information for predicting the fragmentation prospect of a stone.

Glycosaminoglycans in urolithiasis.

To determine if there are differences in urinary glycosaminoglycan (GAG) concentrations, 43 stone-forming patients and 37 healthy control subjects of both sexes were studied. Urinary concentrations of calcium, magnesium, creatinine, uric acid and GAGs were determined. GAGs were measured by the Di Ferrante precipitation procedure followed by the Bitter and Muir reaction. Urinary GAG concentration and daily output were significantly lower in stone-forming patients. The present study clearly demonstrates the decreased urinary GAG concentration and excretion in stone-forming patients and suggests an interaction between GAGs and urate that could modify the inhibitory potency of GAGs.

Effect of low doses of deflazacort vs prednisone on bone mineral content in premenopausal rheumatoid arthritis.

Longterm administration of steroid drugs, particularly prednisone, is known to induce osteoporosis, as well as bone growth inhibition and delayed fracture union. Recently deflazacort, an oxazoline prednisone derivative, has been developed to reduce such deleterious effects. We carried out a comparative study in premenopausal patients with rheumatoid arthritis (RA). Sixteen cases whose mean age was 36.5 years and mean disease duration 29 months, all fulfilling ARA criteria, were evaluated in a randomized, double blind trial. Visually identical deflazacort or prednisone capsules were given and patients were instructed to maintain an adequate calcium intake. Laboratory tests focussed on bone mineral density in lumbar spine, femoral neck and Ward's triangle and whole body mineral content. Differences between baseline and 12-month values were processed statistically. Persistent synovitis control proved similar for both drugs and features suggestive of Cushing's syndrome were only found in the prednisone group. The difference in whole body bone mineral content between the deflazacort and prednisone groups just failed to reach statistical significance. In the deflazacort group, the difference between the nonsignificant bone mineral density increase at the femoral neck and the significant decrease in the prednisone group proved statistically significant. Ward's triangle was the most sensitive area to bone mineral density changes in patients receiving prednisone, with a highly significant intergroup difference (p < 0.01). We believe this is the first study on corticosteroid induced osteoporosis, as evaluated by whole body mineral content measurements in premenopausal patients with short term RA, showing that deflazacort is a promising alternative in cases severe enough to require steroid therapy.

Excreción urinaria de sodio y magnesio en la hipercalciuria idiopática / Sodium and magnesium urinary excretion in idiopathic hypercalciuria

Se estudió la excreción urinaria de sodio y magnesio en sujetos normales y en pacientes con hipercalciuria renal y absortiva, bajo una dieta de 1200mg de calcio por día. Los valores de calcio, sodio y magnesio séricos no mostraron diferencias entre los tres grupos. En orina de 24h no se encontraron diferencias en la excreción de sodio y magnesio, y se verificó una correlación significativa entre las excreciones de calcio y sodio y calcio y magnesio en todos los grupos. En orina de ayunas los pacientes con hipercalciuria renal mostraron una excreción de sodio y magnesio significativamente superior a los absortivos y el grupo control, y solo el grupo renal mostró significativas correlaciones entre las excreciones de calcio y sodio y calcio y magnesio. Los resultados sugieren una anormalidad concurrente en el manejo tubular del calcio, el sodio y el magnesio en el grupo de pacientes con hipercalciuria renal (AU)

Excreción urinaria de sodio y magnesio en la hipercalciuria idiopática. / [Urinary excretion of sodium and magnesium in idiopathic hypercalciuria]

We have studied urinary sodium and magnesium excretion in 30 normal subjects (15 women and 15 men, mean age 43 +/- 14 years, mean weight 74 +/- 18 Kg) and in 60 hypercalciuric stone-forming patients, 30 with renal hypercalciuria (HR) (15 women and 15 men, mean age 39 +/- 10 years, mean weight 71 +/- 16 Kg) and 30 with absorptive hypercalciuria (HA), (15 women and 15 men, mean age 41 +/- 13 years, mean weight 69 +/- 12 Kg). The diagnosis of hypercalciuria and the classification in HA and HR was made with our ambulatory study protocol. Hypercalciuria was defined by a daily calcium excretion above 300 mg (men) or 220 mg (women), and patients with fasting calcium to creatinine ratio, and calcium per 100 ml of glomerular filtrate average value above 0.11 were considered to have HR. Control subjects and hypercalciuric patients were maintained on a diet containing 1200 mg Ca, 800 mg P, 200 mg Mg and 100 mmol Na per day for a 7-day period. Two 24-hour urine samples were collected on days 6 and 7 of this diet. On the morning of day 8, following a 12-hour fast, 300 ml of distilled water was drunk and a 2-hour urine sample was collected. A blood sample was taken halfway this time. In all blood and urine samples, calcium, magnesium, sodium, phosphorus and creatinine were quantified. Creatinine clearance and calcium, sodium and magnesium per 100 ml of glomerular filtrate were calculated from these determinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Saturación urinaria con oxalato de calcio en urolitiasis / Urine saturation with calcium oxalate in urolithiasis

Mediante un programa de computación iterativo se calculó el Producto de Actividad (PA) del oxalato de calcio (OxCa) con datos de orina de 24 h de 30 pacientes litiásicos formadores de cálculos de OxCa y 30 controles sanos. Los resultados muestran una diferencia estadísticamente significativa entre los valores medios de ambos grupos, tanto en el PA como en la concentración urinaria de calcio, magnesio, citrato y oxalato. La mayor contribución relativa del oxalato y el citrato en el aumento y descenso, respectivamente, del PA es puesta de manifiesto. Se confirma la utilidad del cálculo del PA para establecer el riesgo aumentado de formar cálculos y el seguimiento del tratamiento instaurado (AU)