Marie-Claude Faugere

The use of deferoxamine in the management of aluminium accumulation in bone in patients with renal failure.

Aluminum frequently accumulates in patients with end-stage renal failure. We investigated the value of long-term, intermittent infusions of deferoxamine for the removal of aluminium from bone in seven patients undergoing long-term maintenance dialysis. Transient rises in serum aluminum levels occurred initially after treatment. Three patients who were studied by bone biopsy had absent or reduced levels of bone aluminum. Histologic studies of bone before and after therapy showed differences similar to those observed between patients with uremia who had an accumulation of aluminum in bone and those who did not. The diagnostic value of rises in the serum aluminum level after a single infusion of deferoxamine was studied in 12 patients with and 10 patients without aluminum accumulation in bone. All patients with bone aluminum had rises in serum aluminum levels, but rises were also observed in some patients without bone aluminum. Thus, the test cannot be used to diagnose aluminum accumulation in bone. Urinary aluminum levels increased significantly after a single infusion of deferoxamine in three patients with kidney transplants and accumulation of aluminum in bone. These findings indicate that deferoxamine is beneficial for the therapy of aluminum accumulation in the bone of patients with renal failure.

Treatment with pyrophosphate inhibits uremic vascular calcification

Pyrophosphate, which may be deficient in advanced renal failure, is a potent inhibitor of vascular calcification. To explore its use as a potential therapeutic, we injected exogenous pyrophosphate subcutaneously or intraperitoneally in normal rats and found that their plasma pyrophosphate concentrations peaked within 15 min. There was a single exponential decay with a half-life of 33 min. The kinetics were indistinguishable between the two routes of administration or in anephric rats. The effect of daily intraperitoneal pyrophosphate injections on uremic vascular calcification was then tested in rats fed a high-phosphate diet containing adenine for 28 days to induce uremia. Although the incidence of aortic calcification varied and was not altered by pyrophosphate, the calcium content of calcified aortas was significantly reduced by 70%. Studies were repeated in uremic rats given calcitriol to produce more consistent aortic calcification and treated with sodium pyrophosphate delivered intraperitoneally in a larger volume of glucose-containing solution to prolong plasma pyrophosphate levels. This maneuver significantly reduced both the incidence and amount of calcification. Quantitative histomorphometry of bone samples after double-labeling with calcein indicated that there was no effect of pyrophosphate on the rates of bone formation or mineralization. Thus, exogenous pyrophosphate can inhibit uremic vascular calcification without producing adverse effects on bone.

Aluminum-Related Bone Disease in Mild and Advanced Renal Failure: Evidence for High Prevalence and Morbidity and Studies on Etiology and Diagnosis

To study aluminum-related bone disease, bone biopsies and serum biochemical measurements were done in 97 patients on maintenance dialysis and in 100 patients with mild to moderate renal failure. Bone histology, histochemical staining for aluminum and determination of bone aluminum content were done. Stainable bone aluminum was found in 50% of dialyzed patients and in 5% of nondialyzed patients. The finding of stainable bone aluminum in dialyzed patients was associated with high morbidity and mortality; it was not only seen in most patients with low turnover osteomalacia, but also in 47% of patients with mixed uremic osteodystrophy and in 1 patient with predominant hyperparathyroid bone disease. Patients with stainable aluminum had lower bone mass and decreased activity of bone-forming and -resorbing cells. Cumulative doses of aluminum-containing phosphate binders were a major risk factor. Aluminum in drinking water represents an additional risk factor. Neither serum biochemical tests nor single infusion of deferoxamine could be employed as diagnostic tools. Bone biopsies were the only means for diagnosis.

Calcitriol, parathyroid hormone, and accumulation of aluminum in bone in dogs with renal failure.

Accumulation of aluminum in bone is a frequent finding in patients requiring chronic dialysis and is associated with considerable morbidity and/or mortality. Until now, evidence seemed to point to relatively low circulating levels of parathyroid hormone as a contributing factor, but because levels of parathyroid hormone and calcitriol are interrelated, calcitriol might be also involved. In this study we employed an animal model to evaluate the single and combined effects of parathyroid hormone and calcitriol on bone aluminum accumulation. The results show significantly less aluminum accumulation in calcitriol-replete dogs independent of the presence or absence of parathyroid hormone. These results indicate that low levels of calcitriol may play a role in the development of aluminum related bone disease. Further studies are needed to demonstrate whether administration of calcitriol in patients with renal insufficiency will prevent development of aluminum-related bone disease.

Aluminum-Related Bone Disease

Only rather recently has the biologic and pathogenetic relevance of aluminum, this most common metal come under serious scientific scrutiny. Various laboratory findings of accumulations of aluminum in the brain, kidney, liver, parathyroid glands, skeletal muscle, heart, lungs, pancreas and spleen as well as stainable aluminum in bone have spurred widespread interest in aluminum absorption and toxicity and in the mechanisms involved in the metabolism of aluminum. Since the kidney is the major excretory organ for aluminum, this report focuses on the abnormalities occurring with aluminum accumulation in the bone of patients with renal failure to determine the metabolic interrelationships of aluminum, parathyroid hormone, vitamin D, iron, and calcium. This editorial presents an overview of the most recent investigations of aluminum accumulation in humans, experimental animal models, and at the cellular level, presents the metabolic relationships known to exist as well as those strongly suggested in documented studies, and identifies those aspects of aluminum-related bone disease awaiting study in this increasingly important field of inquiry. The study outlines the metabolism of aluminum, the pathogenesis, prevalence, morbidity and mortality of aluminum-related bone disease, the histopathology of bone with aluminum accumulation, the recognized difficulties inherent in the diagnosis of aluminum-related bone disease, and the current understanding as relates to prevention and therapy.

Five-year postoperative results of cemented femoral arthroplasty in patients with systemic bone disease

To determine whether bone cellular abnormality affects the results of cemented femoral arthroplasty, 21 patients had biopsies of the iliac crest and femoral cortex at the time of surgery. Roentgenographic and histomorphometric studies were used to characterize fibrous membrane formation, cancellous bone, calcar resorption, and bone turnover. Patients with high bone turnover and decreased femoral thickness and density before surgery were at risk of developing calcar resorption and cancellous diaphyses, conditions that weaken proximal stem support and lead to early failure. These findings suggest that noncemented stems may be indicated in this group. Another group, osteoporotic patients, suffered from osteoblastic insufficiency, which may be the indication for the use of cemented stems rather than noncemented stems, which require bony ingrowth.

The Effect of Class A Scavenger Receptor Deficiency in Bone

Class A scavenger receptor (SR-A) is predominantly expressed by macrophages, and because osteoclasts are of monocyte/macrophage lineage, SR-A is of potential interest in osteoclast biology. In addition to modified low density lipoprotein uptake, SR-A is also important in cell attachment and signaling. In this study we evaluated the effect of SR-A deletion on bone. Knock-out animals have 40% greater body weight than wild type. Body composition analyses demonstrated that total lean and fat body mass were greater in knock-out animals, but there was no significant difference in percent fat and lean body mass. Bone mineral density and content were significantly greater in knock-out compared with wild type animals. Micro-computed tomography analyses confirmed that total volume, bone volume as well as trabecular number, thickness, and connectivity were significantly greater in knock-out mice. As expected, trabecular separation was greater in wild type mice. The phenotype appears to be explained by 60% fewer osteoclasts in females and 35% fewer in males compared to wild type mice with a paradoxical increase in nuclei/osteoclast in knock-out animals. Furthermore, there were no differences in adipocyte number and osteoblast number or activity. The addition of the soluble extracellular domain of SR-A to RAW264.7 cells stimulated a concentration-dependent increase in osteoclast differentiation that was receptor activator of nuclear factor-κB ligand (RANKL)-dependent. Soluble SR-A had no effect on cell proliferation in the presence of RANKL but stimulated a 40% increase in numbers in the absence of RANKL. We conclude that SR-A plays a role in normal osteoclast differentiation, suggesting a novel role for this receptor in bone biology.

Aluminum: Toxin or Innocent Bystander in Renal Osteodystrophy

LIMITED information is available on quantitative changes of static and dynamic histologic parameters of bone found with accumulation of aluminum in bone. It was recently postulated that aluminum deposition in bone might represent an epiphenomenon. In addition, it is controversial whether aluminum accumulation in bone can be diagnosed by noninvasive means. 1.2 Therefore, a careful description and evaluation of diagnostic means and of the relationship between aluminum and bone abnormalities is warranted.

Histomorphometric analysis of tricalcium phosphate ceramic implanted into Turkeys

Porous cylinders of tricalcium phosphate of two pore size distributions and four pore densities were implanted bilaterally into the ulnae of twelve skeletally mature turkeys. Morphometric analyses at two, four, and six post-operative months indicate implant resorption begins prior to the second post-operative month and that physical changes and biologic response continue at a rate dependent upon pore size distribution.

Oxalosis in Bone Causing a Radiographical Mimicry of Renal Osteodystrophy

We report a patient on maintenance dialysis with oxalosis and radiographical signs typical of hyperparathyroid bone disease in patients with end-stage renal insufficiency. The patient underwent a subtotal parathyroidectomy. Because his bone pain worsened during long-term dialytic therapy, a bone biopsy was performed and revealed crystalline deposits in trabecules and the bone marrow characteristic of oxalate. Trabecular destruction and signs of defective mineralization of bone were also found. When the diagnosis was made, the patient had become addicted to narcotic analgesics; he died from an overdose. The case underscores the limits of skeletal radiographs for the diagnosis of oxalosis in bone. Furthermore, the radiographic findings may lead to erroneous conclusions in patients with renal osteodystrophy because the radiographic signs of oxalosis can mimic those of hyperparathyroid bone disease.