Low bone turnover in patients with renal failure.

Renal failure inevitably leads to metabolic bone disease. Low turnover disease or adynamic bone disease (ABD) is characterized by a low number of osteoblasts with normal or reduced numbers of osteoclasts. Mineralization proceeds at a normal rate, resulting in normal or decreased osteoid thickness. Recently, it became clear that the relative contribution of the various types of renal osteodystrophy (ROD) to the spectrum of the histologic picture in renal failure patients underwent profound changes during the last 25 years. At the moment, the exact physiopathological mechanisms behind ABD are not yet elucidated, and thus the reason(s) for its increasing prevalence remains poorly understood. A number of epidemiological and experimental data suggest a multifactorial pathophysiologic process, in which hypoparathyroidism and suppression of the osteoblast are the main actors. Compared to adynamic bone disease, osteomalacia has now become a much rarer disease (around 4%), at least in Western countries. On the other hand, recent studies indicate that this particular bone disease entity might still regularly occur in less developed countries. Osteomalacia originates from a direct effect on the mineralization process. With this type of renal bone disease, the effects of secondary hyperparathyroidism on bone are overridden by a number of metabolic abnormalities that finally result in a defective bone mineralization, as occurs, for instance, when the lag time between osteoid deposition and its mineralization is increased. The relationship between exogenous and endogenous vitamin D deficiency (mainly calcitriol) and the histologic finding of osteomalacia in uremic patients is well known. Recent data showed distinctly lowered 25-(OH) vitamin D3 levels in the presence of unaffected calcitriol concentrations in patients with osteomalacic lesions, as assessed radiologically by the presence of Looser's zones. Recently, we found that bone strontium levels were increased in patients with osteomalacia as compared to all other types of ROD. Strontium accumulation appeared to originate mainly from the use of strontium-contaminated dialysate, which resulted from the addition of strontium-containing acetate-based concentrates. Evidence for a causal role of the element in the development of a mineralization defect could be tested experimentally by adding strontium to drinking water in a chronic renal failure rat model.

Increased serum strontium levels in dialysis patients: an epidemiological survey.

BACKGROUND: We previously reported on increased bone strontium levels in dialysis patients with osteomalacia versus those presenting other types of renal osteodystrophy. A causal role of strontium in the development of osteomalacia was established in a chronic renal failure rat model. METHODS: To further elucidate the latter issue and to find out whether dialysis patients from particular centers/countries are at an increased risk for strontium accumulation, a worldwide multicenter study was established. In total, 834 patients from 34 dialysis centers in 23 countries were included. In each of the patients, a serum sample was taken for strontium determination, and water and dialysate samples were taken at the various steps of the water purification process. For each patient clinical data and for each center dialysis modalities were recorded. RESULTS: Strontium levels in serum of dialysis patients showed major differences between the various centers, ranging from mean values of 25 +/- 8 microgram/liter in the center with the lowest level up to 466 +/- 90 microgram/liter in the center with the highest concentration. It is of interest that these high levels were mainly found in developing countries. Furthermore, our data point toward a role of the final dialysate in the accumulation of the element, as indicated by the strong correlation (r = 0.74, P < 0.001) between mean serum and dialysate strontium levels. As the high tap water concentration of strontium was adequately reduced during the water purification process, contamination of the final dialysis fluid occurred by the addition of concentrates contaminated with strontium. Besides the dialysate, other factors, such as duration of dialysis, vitamin D supplements, or types of phosphate binders, played a less important role in the accumulation of the element. CONCLUSIONS: Data of this multicenter study indicate patients of particular dialysis centers to be at an increased risk for strontium accumulation, the clinical consequence of which is under current investigation.

Measurement of strontium in serum, urine, bone, and soft tissues by Zeeman atomic absorption spectrometry.

To study the possible accumulation of Sr in chronic renal failure patients, methods were developed for the determination of the element in serum, urine, bone, and soft tissues by using Zeeman atomic absorption spectrometry. Serum samples were diluted 1:4 with a Triton X-100-HNO3 mixture, whereas urine samples were diluted 1:20 with HNO3. Bone samples were digested with concentrated HNO3 in stoppered polytetrafluoroethylene (Teflon) tubes, whereas soft tissues were dissolved in a tetramethylammonium hydroxide solution in water. For serum and urine we used matrix-matched calibration curves, whereas bone and tissue samples were measured against aqueous calibrators. Atomization was performed from the wall of pyrolytically coated graphite tubes for all of the matrices under study. Both inter- and intraassay CVs were <6% (n = 12, n = 10, respectively), and the recovery of added analyte was close to 100% for all of the biological matrices under study. Detection limits were 1.2 microg/L (serum), 0.3 microg/L (urine), 0.4 microg/g (bone), and 2.2 ng/g (soft tissues), whereas the sensitivity determined by the slope of the calibration curve, i.e., the amount of Sr producing a 0.0044 integrated absorbance change in signal, was 2.4 pg, 2.4 pg, 3.9 pg, and 2.6 pg for these matrices respectively. We conclude that the present methods are precise and accurate and easily applicable for both routine use and research investigations. They will allow us to study the metabolism of the element in chronic renal failure patients and shed some light on the association that was recently noted between increased bone Sr concentrations and the development of osteomalacia in these individuals.

Increased bone strontium levels in hemodialysis patients with osteomalacia.

BACKGROUND: In this study, we report on the association between increased bone strontium levels and the presence of osteomalacia in end-stage renal failure patients treated by hemodialysis. METHODS: We performed a histologic examination and determined the strontium content and strontium/calcium ratios in bone biopsies of 100 hemodialysis patients recruited from various centers all over the world. Aside from the bone strontium concentration, the bone aluminum content was assessed. The bone zinc concentration, a nonrelevant element for bone toxicity, was also measured. RESULTS: Bone strontium levels and bone strontium/calcium ratios were increased in subjects with osteomalacia when compared with those with the other types of renal osteodystrophy. Bone strontium and bone calcium levels correlated with each other. The slope of the linear regression curve correlating these parameters was much steeper in the osteomalacic group (Y = 2.22X - 120) as compared with the other types of renal osteodystrophy (Y = 0.52X - 5.7). Within the group of patients with osteomalacia, bone strontium levels also significantly correlated with the bone aluminum content (r = 0.72, P = 0.018). No such correlation was found for the other types of renal osteodystrophy. The bone zinc concentration of subjects with normal renal function did not differ significantly from the values noted for the various types of renal osteodystrophy taken as separate groups, nor could increased bone zinc concentrations be associated with a particular bone lesion. CONCLUSIONS: Our data demonstrate an association between osteomalacia and increased bone strontium concentrations in dialysis patients. Further studies are warranted to establish whether strontium plays either a primary, secondary, or contributive role in the development of the latter type of renal osteodystrophy.

Strontium causes osteomalacia in chronic renal failure rats.

BACKGROUND: We recently reported an association between increased bone strontium (Sr) levels and osteomalacia in dialysis patients. METHODS: To delineate whether or not Sr acts as a causal factor in the development of osteomalacia, we devised the following study: four groups of chronic renal failure (CRF) rats were given Sr, aluminum (Al), both of these compounds or none of the elements (controls). RESULTS: Administration of Sr and/or A1 resulted in increased bone levels of the respective elements. Histological examination revealed impairment of mineralization in the Sr group and to a lesser extent in the Al group as compared to the control group. There was also a significant increase in osteoid area in the Sr group, but not in the Al group. No differences in bone surface or erodic perimeter were noted between the various study groups. Histochemically, Sr could be localized in calcified bone, mainly in new bone close to the osteoid/calcification front, a critical site of bone mineralization. Histochemical findings were confirmed by electron probe X-ray microanalysis. CONCLUSIONS: These findings indicate that Sr accumulation in chronic renal failure rats resulted in the development of osteomalacic lesions, in contrast to the Al group where adynamic bone disease was induced in the present set-up. Further studies are required to define the mechanism by which way Sr causes osteomalacia in chronic renal failure rats.

Aluminum, iron, lead, cadmium, copper, zinc, chromium, magnesium, strontium, and calcium content in bone of end-stage renal failure patients.

BACKGROUND: Little is known about trace metal alterations in the bones of dialysis patients or whether particular types of renal osteodystrophy are associated with either increased or decreased skeletal concentrations of trace elements. Because these patients are at risk for alterations of trace elements as well as for morbidity from skeletal disorders, we measured trace elements in bone of patients with end-stage renal disease. METHODS: We analyzed bone biopsies of 100 end-stage renal failure patients enrolled in a hemodialysis program. The trace metal contents of bone biopsies with histological features of either osteomalacia, adynamic bone disease, mixed lesion, normal histology, or hyperparathyroidism were compared with each other and with the trace metal contents of bone of subjects with normal renal function. Trace metals were measured by atomic absorption spectrometry. RESULTS: The concentrations of aluminum, chromium, and cadmium were increased in bone of end-stage renal failure patients. Comparing the trace metal/calcium ratio, significantly higher values were found for the bone chromium/calcium, aluminum/calcium, zinc/calcium, magnesium/calcium, and strontium/calcium ratios. Among types of renal osteodystrophy, increased bone aluminum, lead, and strontium concentrations and strontium/calcium and aluminum/calcium ratios were found in dialysis patients with osteomalacia vs the other types of renal osteodystrophy considered as one group. Moreover, the concentrations of several trace elements in bone were significantly correlated with each other. Bone aluminum was correlated with the time on dialysis, whereas bone iron, aluminum, magnesium, and strontium tended to be associated with patient age. Bone trace metal concentrations did not depend on vitamin D intake nor on the patients' gender. CONCLUSIONS: The concentration of several trace elements in bone of end-stage renal failure patients is disturbed, and some of the trace metals under study might share pathways of absorption, distribution, and accumulation. The clinical significance of the increased/decreased concentrations of several trace elements other than aluminum in bone of dialysis patients deserves further investigation.