Aluminum-induced Bone Disease Research Articles

No association between the aluminium content of trabecular bone and bone density, mass or size of the proximal femur in elderly men and women

BackgroundAluminium is considered a bone toxic metal since poisoning can lead to aluminium-induced bone disease in patients with chronic renal failure. Healthy subjects with normal renal function retain 4% of the aluminium consumed. They might thus also accumulate aluminium and eventually be at risk of long-term low-grade aluminium intoxication that can affect bone health.MethodsWe therefore examined 62 patients with femoral neck fractures or osteoarthritis of the hip (age range 38–93), with the aim of examining whether aluminium in bone is associated with bone-mineral density (BMD), content (BMC) or width of the femoral neck measured by dual-energy X-ray absorptiometry (DXA). During operations bone biopsies were taken from the trabecular bone of the proximal femur. The samples were measured for their content of aluminium using a mass spectrometer.ResultsNo significant association between the aluminium content in bone and femoral neck BMD, BMC or width could be found after multivariate adjustment.ConclusionOur results indicate that the accumulated aluminium content in bone during life does not substantially influence the extent of osteoporosis.

The aluminum content of bone increases with age, but is not higher in hip fracture cases with and without dementia compared to controls

Aluminum is considered a potentially toxic metal, and aluminum poisoning may lead to three types of disorders: aluminum-induced bone disease, microcytic anemia and encephalopathy. This is well known in patients with chronic renal failure, but since healthy subjects with normal renal function retain 4% of the aluminum consumed, they are also at risk of long-term low-grade aluminum intoxication. Included in this study were a total of 172 patients (age range 16-98 years) with the aim of examining whether aluminum accumulates in bone with increasing age. Additionally, we aimed to investigate whether the aluminum content of bone differs between controls and hip fracture cases with and without dementia, in particular in those with Alzheimer's disease. During operations for all cases, bone biopsies were taken with an aluminum-free instrument from the trabecular bone. The samples were measured for their content of aluminum using an inductively coupled mass spectrometer. We found an exponential increase in aluminum content of bone with age. The average aluminum values, adjusted for age, were similar in men and women (P=0.46). No significant differences in sex- and age-adjusted mean aluminum values between the controls and the hip fracture cases with (P=0.72) and without (P=0.33) dementia could be detected. The average aluminum concentration among cases with Alzheimer's disease was also similar to the values of hip fracture patients with other types of dementia (P=0.47). Odds ratios of hip fracture for each quartile of aluminum content in bone were also estimated to detect non-linear effects, but we did not find any statistically significant association remaining after age and sex adjustment. Thus, our results indicate that we accumulate aluminum in bone over our life span, but this does not seem to be of major pathogenetic significance for the occurrence of hip fracture or dementia.

Renal Osteodystrophy

The main forms of renal osteodystrophy are secondary hyperparathyroidism, aluminum-induced bone disease and adynamic bone disease without aluminum intoxication. Aluminum intoxication has become rare because of control of the dialysate solution and avoidance of aluminum containing phosphate binders. Secondary hyperparathyroidism still develops early in the course of renal failure and remains the most frequent form of osteodystrophy in patients treated by maintenance hemodialysis. Several factors, including hyperphosphatemia and deficient synthesis of 1,25-dihydroxyvitamin D are involved in its pathogenesis. Secondary hyperparathyroidism is symptomatic only in severely affected patients. Prevention depends on control of serum phosphorus +/- prescription of 1-alpha-hydroxylated vitamin D derivatives or may require subtotal parathyroidectomy when hyperparathyroidism is refractory.Adynamic bone disease not related to aluminum intoxication has been increasingly recognized in recent years and is presently the most frequent form of osteodystrophy in continuous ambulatory peritoneal dialysis patients. This condition, characterized by low bone turnover and depression of bone formation, appears to be associated with an increased risk of bone fracture. The main pathophysiologic feature is excessive treatment of hyperparathyroidism leading to hypoparathyroidism. Serum immunoreactive 1,84-parathormone levels should therefore be kept at a level of 1.5-fold to 3-fold the upper limit of normal in patients treated by maintenance hemodialysis.

Aluminium-induced bone disease in uremic rats: effect of deferoxamine.

We have previously established a rat model of chronic uremia, which is suitable to investigate the effect of various treatment modalities on renal osteodystrophy [1]. After four months subsequent to 5/6 nephrectomy, some animals were treated by gavage for 9 weeks with tap water (controls), or with aluminium (Al-citrate) 3 x 25 mg/week/kg b.wt +/- subsequent deferoxamine (DFO) 3 x 50 mg/week/kg b.wt. for 4 weeks. At termination of the study, serum clinical chemistry, femoral chemical composition and mechanical properties, calvarial parathyroid hormone (PTH)-elicited adenylate cyclase (AC) and phospholipase C (PLC) activities, cross-sectional femoral area, as well as bone histomorphometry, were analyzed. Animals given Al displayed moderately enhanced serum Al and bone Al accumulation, however, DFO-treatment did not fully alleviate bone Al retainment. A small increase in serum PTH was seen in all animals rendered uremic. Furthermore, a marked fall in serum alkaline phosphatase (ALP) below normal controls was observed in Al +/- DFO-treated animals compared with uremic controls. The uremic condition led to reduced femoral ratios of hydroxyproline (HYP) over Ca(2+) and phosphate (P(i)), while Al-intoxication alone enhanced femoral Hyp contents above values seen for normal controls. The protracted ureamia caused a deterioration of long bone resilience and brittleness, however, Al +/- DFO-treatment seemed to normalize the latter. Contrastingly, Al +/- DFO-gavage enhanced time to fracture. Uremic rats intoxicated with Al showed a complete loss of calvarial PTH-sensitive AC and PLC activities. DFO-treatment normalized PTH-elicited PLC, while PTH-susceptible AC remained super-normal. Al apparently exerts a long term down-regulation of both PTH-sensitive signaling systems as evidenced by studies of rat UMR 106 osteosarcoma cells in culture. The uremic condition enhanced endosteal bone resorption as shown by femoral shaft dimension analysis, while Al +/- DFO-treatment insignificantly reversed the condition. Finally, histomorphometrical analyses showed that DFO-administration tended to normalize aberrant trabecular bone volume, while rectifying both bone resorption and degree of mineralization. In conclusion, we assert that Al-intoxication hampers both processes (i.e. formation and resorption) of bone turnover, and that DFO-treatment to a certain extent prevents the uremia- and Al-induced bone disease in rats.

Effect of aluminium on the development of hyperparathyroidism and bone disease in the azotaemic rat

Aluminium toxicity in dialysis patients is associated with a relative parathyroid hormone (PTH) deficiency as well as osteomalacia. In-vitro studies of parathyroid cells have shown that aluminium inhibits PTH secretion. However, only limited data are available on how aluminium affects the development of hyperparathyroidism in the azotaemic animal. Four groups of azotaemic rats were studied; in each group, renal failure was induced by a two-stage 5/6 nephrectomy, after which rats were studied for 40 days. In three groups hyperparathyroidism was stimulated by the use of a high phosphorus (1.2%) diet (HPD). The four groups were (1) HPD; (2) HPD + high-dose aluminium (HDAL)--1.5 mg of aluminium was administered intraperitoneally (IP) 5 days per week; (3) HPD + low-dose aluminium (LDAL)--0.5 mg of aluminium was administered IP 5 days per week; and (4) moderate phosphorus (0.6%) diet (MPD); the MPD group was used to control hyperparathyroidism and thus provide a comparison of PTH levels and azotaemic bone disease. After 40 days, the serum PTH level was higher (P < 0.05) in the HPD + HDAL group (37 +/- 2 pmol/l) than the HPD, HPD + LDAL, and MPD groups (24 +/- 3, 28 +/- 4, and 6 +/- 1 pmol/l respectively). The correlation between serum PTH and calcium, serum PTH and phosphorus, and serum calcium and phosphorus was significant for the four groups (P < 0.02); however, the relationship between serum PTH and calcium, and between serum calcium and phosphorus was altered in the HPD + HDAL group (serum aluminium 30.8 +/- 2 mumol/l). Aluminium administration induced a decrease (P < 0.05) in the bone formation rate and the adjusted apposition rate, and an increase (P < 0.05) in osteoid volume and the mineralization lag time. Despite aluminium administration, diet-induced hyperparathyroidism resulted in an increase (P < 0.05) in the osteoblast surface. In conclusion, in the azotaemic rat (1) aluminium did not slow the development nor decrease the magnitude of hyperparathyroidism; (2) aluminium appeared to alter the relationship between serum PTH and calcium, and between serum calcium and phosphorus; (3) hyperparathyroidism changed the expression of aluminium-induced bone disease and may afford the bone some protection against the toxic effects of aluminium.

Effect of fluoride on aluminum-induced bone disease in rats with renal failure.

Aluminum (Al) accumulation in renal failure is an etiological factor in the pathogenesis of low turnover bone disease. Aluminum-induced impairment of mineralization has been related to a reduced extent of active bone-forming surface. The present study investigated the effect of fluoride, a potent stimulator of osteoblast number, on the toxicity of aluminum in rats with renal failure (Nx). Following a large parenteral aluminum load (3.2 mg/kg x day) over a period of nine weeks, bone histomorphometry of vertebral cancellous bone revealed a severe low-turnover osteodystrophy as evidenced by a fall in osteoblastic osteoid surfaces and mineral apposition rates. Concurrent administration of fluoride [20 mg/liter (F20) or 40 mg/liter (F40) supplied with the drinking water] resulted in a significant increase in the number of osteoblasts (Nx+Al+F40 vs. Nx+Al, 33.75 +/- 2.83 vs. 1.81 +/- 0.43 mm-1, P less than 0.001) together with an overall reduced deposition of aluminum in bone (469.3 +/- 24.6 vs. 592.2 +/- 28.3 micrograms/g, P less than 0.01). However, there was an increase in the fraction of osteoid surface exhibiting stainable aluminum at the bone-osteoid interface (70.7 +/- 7.1 vs. 44.3 +/- 6.0%, P less than 0.005). Fluoride-exposed rats accumulated a significantly larger osteoid volume, suggesting an exacerbation of the osteomalacic lesion, and furthermore, dynamic histomorphometric parameters remained depressed. These results indicate that fluoride has a distinct effect on the pattern of aluminum deposition in bone. In addition, fluoride antagonizes the aluminum-induced reduction in osteoblast number but provides no amelioration of the impaired mineralization in aluminum-intoxicated rats. Thus, in this model a decrease in the extent of osteoblast surface does not account for the development of aluminum-related bone disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Solitary, spontaneous cervical and large bone fractures in aluminum osteodystrophy

Aluminum-induced bone disease in uremic patients receiving dialysis was first described a little more than 10 years ago. The epidemic form of the disease was seen in centers where there was a high aluminum content in the water dialysate. Although this problem has been corrected, sporadic forms of the disease continue to be noted in dialyzed and nondialyzed patients. Multiple fractures are a radiological feature of aluminum-related bone disease. Fractures of the ribs and hips and vertebral crush fractures are the usual manifestations. We present four patients whose nontraumatic fractures involved large bones, without evidence of multiple fractures. In two of the patients symptoms were vague and subacute; a third patient with a subcapital fracture was ambulatory. Only in one patient (fractured dens) were symptoms acute enough to warrant immediate radiography. One of the patients had no symptoms pertaining to a fracture of C5 with retrolisthesis. Rib fractures are common in this condition but were seen in only one patient, in whom they were detected 8 years previously. Healing was not seen in any of the fractures. In patients receiving dialysis the presence of spontaneous fractures of large bones or cervical vertebrae, which may be clinically silent or vaguely symptomatic, should raise the possibility of aluminum-induced osteomalacia even if these fractures are solitary.

Vitamin D, desferrioxamine and aluminum-induced bone disease in uremic rats.

The effect of 100 ng 1 alpha-OH vitamin D/week alone and in combination with desferrioxamine (DFO), 150 mg/week, was evaluated in aluminum loaded uremic rats. Vitamin D (Vit D) caused an increase of Al in muscle and a decrease in serum Al. Bone histology showed mineralization defect and an increase in bone mass, due to an increase in unmineralized bone, induced both by Al and Vit D administration. Treatment with DFO enhanced urinary Al excretion and lowered tissue Al, without inducing major changes of static bone histology. It is concluded that in Al-loaded uremic rats Vit D can redistribute body Al and that both Al and Vit D can cause a mineralization defect. A 6-week treatment with DFO lowers tissue Al without changing significantly static bone parameters.

Risk of Aluminium Intoxication in Long-term Acetate Redy Dialysis

Closed-circuit dialysis using the Redy sorbent cartridge to regenerate the dialysate has been incriminated in previous reports as a cause of severe fracturing osteomalacia and fatal encephalopathy in several patients treated with this procedure for 15-36 months. In a retrospective study, we compared 15 unselected patients who had received Redy dialysis for 66 +/- 14 months with 15 control patients dialysed with single passage of dialysate. Redy and control patients were matched for age, sex, and duration of dialysis. They belonged to two dialysis centres, situated in the same geographical area and having a common water supply. Mean serum and bone aluminium concentrations were slightly greater in the Redy group but the differences were not significant. Pathological fractures had occurred in two Redy patients and in one control, but could not be attributed to aluminium-induced bone disease. Although the histochemical staining for aluminium in bone was positive in six patients, diagnosis of aluminium-induced bone disease was made in one case only. The results of bone histomorphometry did not differ significantly between the two groups. Our findings may be explained by the strict application of the measures required to avoid aluminium contamination of the Redy dialysate, i.e. sufficient rinsing before dialysis, use of almost aluminium-free water, and of acetate-buffered dialysate.

Bone lead in dialysis patients

We measured lead and calcium in multiple bone biopsies from 11 cadavers without known excessive past exposure to lead. Paired iliac crest, transiliac and tibial bone biopsies from these cadavers indicated that in bone biopsy specimens the lead/calcium ratio is more reproducible than the absolute lead concentration. There were no significant differences between the lead/calcium ratios from the iliac crest, transiliac, or tibial specimens. Transiliac bone biopsies from 35 patients (13 patients showing symptoms of slight or moderate degree of renal failure, medical history of gout and/or arterial hypertension and 22 lead workers with chelatable lead in excess of 1000 micrograms) indicated that the lead and the lead/calcium ratio in bone biopsies reflect body lead stores as estimated by the EDT A test (r = 0.87 and 0.83, respectively). Chemical and histological studies of transiliac biopsies previously obtained from 153 dialysis patients (from 8 dialysis centers from Belgium, France and Germany) for studies of aluminum-induced bone disease showed that chronic renal failure and dialysis do not cause accumulation of lead in bone and elevated bone lead does not appear to alter trabecular bone histomorphometry. We found that in 5% of the hemodialysis population studied, bone lead concentrations approximated levels found in active lead workers.

Pathophysiology of aluminum-induced bone disease.

Pathophysiology of aluminum-induced bone disease.

Periosteal new bone in patients on intermittent haemodialysis: An early indicator of aluminium-induced osteomalacia?

Periosteal new bone forming along the distal shafts of the tibia, fibula and pelvic inlet was observed to be an unusual feature in patients on intermittent haemodialysis. Sequential skeletal surveys of 13 patients exhibiting this feature were reviewed and correlated with the biochemical, histological and clinical data. The radiological features comprised periosteal new bone, minimal or no evidence of secondary hyperparathyroidism, sclerosis (not in the classical 'rugger jersey' spine distribution but affecting, particularly, the femoral heads) and, in several patients, numerous fractures, particularly of the ribs. There were 10 patients with osteomalacia, in seven of whom the features were consistent with aluminium-induced bone disease. We suggest that the finding of periosteal new bone in the above distribution in a patient on intermittent haemodialysis should alert the clinician to the possibility of aluminium intoxication.

Release of Aluminum by the Redy Dialysis Cartridge

Perfusion studies in 9 D-31 Redy acetate dialysis cartridges revealed a significant release of aluminum in a form that could diffuse across a dialysis membrane. 8 azotemic patients undergoing dialysis on the Redy system for periods of 18-36 months developed signs and symptoms of aluminum-induced osteomalacic bone disease, and 6 of them also had symptoms and electroencephalographic abnormalities of dialysis encephalopathy. 7 patients have died with these complications. In view of the significant release of aluminum, the D-31 Redy dialysis cartridge may not be ideal or safe for long-term hemodialysis.