Aluminum-related Osteomalacia Research Articles

Comparison of bone formation rates measured by radiocalcium kinetics and double-tetracycline labeling in maintenance dialysis patients

We report 23 prospective studies on 18 maintenance dialysis patients in whom we measured skeletal mineralization rate (m) using 47Ca, analyzed by the expanding pool model, and compared it with the histologic bone formation rate (bfr), volume referent, estimated on tetracycline-labeled iliac crest bone. The patients showed a spectrum of bone disease types including adynamic bone, aluminum-related osteomalacia, and various degrees of secondary hyperparathyroidism. The mean width between double labels, on which mineral apposition rate depended, was estimated using a simple formula relating area to perimeter for each feature enclosed by the labels. Values for m ranged from 0 to 155 mmol calcium per day and for bfr from 0 to 124% per year. There was close correlation between m and bfr (r = 0.976), serum alkaline phosphatase (r = 0.968), and serum immunological parathyroid hormone (iPTH) (r = 0.868). When the volumetric bfr was converted to mass units and applied to the whole skeleton, using literature values for mineral density and cortical and trabecular mass, there was close agreement between the histologic and isotopic estimates of m (r = 0.959). The results validate the two methods and suggest they are interchangeable. However, use of a rigorous method to determine bfr appears to be essential.

Sporadic Aluminum Osteomalacia: Identification of Patients at Risk

Chronic dialysis patients at risk for aluminum osteomalacia in areas of low water-aluminum content are not well identified. We, therefore, studied retrospectively a cohort of 59 patients who underwent bone biopsy at two hospital-based dialysis centers in Montreal (water aluminum content less than 10 micrograms/L). Overall, 25% of patients biopsied had aluminum-related osteomalacia defined by aluminum staining of more than 30% of the trabecular surface and low levels of bone formation as measured by tetracycline labeling. Multiple linear regression analysis showed high predialysis serum creatinine (P less than .05) and the amount of aluminum prescribed per month (P less than .05) as the most important determinants of aluminum staining. We conclude that aluminum-related osteomalacia can be a frequent disease entity in areas of low water-aluminum content. Our findings also suggest predialysis serum creatinine and the amount of aluminum prescribed per month are risk factors for the development of aluminum-related osteomalacia. Though the relationship between serum creatinine and aluminum staining of trabecular bone is unclear, serum creatinine is probably a marker for adequacy of dialysis in these patients.

Results of subtotal parathyroidectomy in hemodialysis patients

In 61 hemodialysis patients undergoing subtotal parathyroidectomy, there was a good correlation between the preoperative serum immunoreactive parathyroid hormone value (iPTH) and the weight of parathyroid tissue removed surgically (p <-0.001). Postoperatively, iPTH decreased rapidly from an initial mean (± SD) of 2,928 ± 1,600 μleq/ml and remained at 365 ± 296 μleq/ml at last follow-up of patients still undergoing hemodialysis (normal, less than 50 μleq/ml). Of six patients who had recurrent hyperparathyroidism (10 percent of total), three required a second subtotal parathyroidectomy. Aluminum-related osteomalacia eventually developed in six patients with bone biopsy-proven hyperparathyroidism before parathyroidectomy. Nine patients with severe fracturing bone disease and hypercalcemia preoperatively but without clear evidence of hyperparathyroidism did not show a favorable response to subtotal parathyroidectomy (high mortality within 28 months, persistence of hypercalcemia, and symptomatic bone disease). Thus, subtotal parathyroidectomy can benefit patients with clearly established severe progressive hyperparathyroidism not responsive to medical therapy but is contraindicated in patients with low iPTH values and no bone biopsy evidence of severe hyperparathyroidism.

Treatment and histological healing of aluminum-related osteomalacia.

Treatment and histological healing of aluminum-related osteomalacia.

Osteomalacia and aplastic bone disease in aluminum-related osteodystrophy.

The bone histology in patients with chronic renal failure and aluminum-related bone disease does not always show the excess accumulation of unmineralized osteoid (matrix) characteristic of osteomalacia. Frequently, bone aluminum accumulation is associated with normal or reduced amounts of unmineralized osteoid and low bone formation and is referred to as aplastic bone disease. In this study, we compared static and dynamic bone histomorphometric parameters and plasma PTH and aluminum levels in 12 patients with osteomalacia and 18 patients with aplastic bone disease who had been receiving dialysis for the same duration to determine if the difference in osteoid accumulation in these 2 lesions might be explained by differences in aluminum accumulation or PTH levels. The stainable bone surface aluminum level was significantly higher in the patients with osteomalacia compared to that in the group with aplastic bone [61 +/- 5% (+/- SEM) vs. 43 +/- 4%; P less than 0.02]. The rates of bone apposition and bone formation were lower in the group with osteomalacia (P less than 0.01). Plasma amino-terminal PTH was not significantly different in the 2 groups. The increment in plasma aluminum levels after a single infusion of deferoxamine was higher in the osteomalacic group than in the aplastic group, suggesting that the patients with osteomalacia accumulated more total body chelatable aluminum than did those with aplastic bone disease during a comparable length of time on dialysis. We conclude that the excess unmineralized osteoid in aluminum-related osteomalacia results from the high rate of total body aluminum accumulation, which directly causes uncoupling of matrix mineralization and matrix production, independent of PTH levels. Patients with aplastic bone disease who have accumulated lesser amounts of total body aluminum fail to develop excess unmineralized osteoid because production and mineralization of matrix are more closely coupled than in the osteomalacic lesion, despite a decline in osteoblast numbers.

Tissue and cellular basis for impaired bone formation in aluminum-related osteomalacia in the pig.

Bone formation is impaired in aluminum-associated bone disease. Reductions in the number of osteoblasts or in the function of individual osteoblasts could account for this finding. Thus, quantitative bone histology and measurements of bone formation were done at three skeletal sites in piglets given aluminum (Al) parenterally, 1.5 mg/kg per d, for 8 wk (Al, n = 4) and in control animals (C, n = 4). Bone Al was 241 +/- 40 mg/kg per dry weight in Al and 1.6 +/- 0.9 in C, P less than 0.001. All Al-treated animals developed osteomalacia with increases in osteoid seam width, osteoid volume, and mineralization lag time at each skeletal site, P less than 0.05 vs. C for all values. Mineralized bone formation at the tissue level was lower in Al than in C, P less than 0.05 for each skeletal site, due to reductions in active bone forming surface. Bone formation at the cellular level was similar in each group, however, and total osteoid production by osteoblasts did not differ in C and Al. Aluminum impairs the formation of mineralized bone in vivo by decreasing the number of active osteoblasts, and this change can be distinguished from the effect of aluminum to inhibit, either directly or indirectly, the calcification of osteoid.

Noninvasive diagnosis of uremic osteodystrophy: uses and limitations.

45 bone biopsies from patients with chronic uremia were reviewed to define which noninvasive investigations were of value in predicting the histological diagnosis and to quantify the spectrum of uremic bone disease at a center that has consistently used an aluminum-free dialysis bath. 17 biopsies were taken postmortem. 15 patients received conservative treatment, the rest were on maintenance dialysis. 13 patients had symptomatic bone disease. Virtually all patients with a uremia duration greater than 3 years had uremic osteodystrophy. All patients with clinical bone disease, hypercalcemia or raised alkaline phosphatase activity had osteodystrophy, but the specific histology was not indicated. Greatly raised parathyroid levels suggested secondary hyperparathyroidism, but the test was only 100% specific when 20 times normal. Total aluminum consumption was highly indicative of bone aluminum concentration (p less than 0.0001) and aluminum-related osteomalacia (5 cases), suggesting that a considerable proportion of uremic bone disease is iatrogenic. Serum aluminum was of some use in the diagnosis of aluminum-related osteomalacia, but was not wholly reliable. Bone mineral content (BMC) using both forearm measurements and total body bone mineral levels (TBBM) were assessed in 32 patients and were found to be reduced in 12, with a preponderance of secondary hyperparathyroidism. BMC and TBBM were negatively correlated to resorbing surfaces and bone formation rate, suggesting that secondary hyperparathyroidism is the uremic bone disease that represents the greatest threat to bone mass. It is concluded that while noninvasive investigations give considerable information, reliable diagnosis requires the use of histological methods.

Elevated Bone Aluminum Content in Dialysis Patients Without Osteomalacia

In almost all dialysis patients, bone aluminum content (BAC) is elevated in comparison with levels in normal subjects. Extremely high BAC (200 micrograms or more of aluminum per gram of bone) is significantly associated with classic aluminum-related osteomalacia. We noted three patients with elevated BAC but without histologic evidence of typical osteomalacia. Two of the patients had moderately severe osteitis fibrosa (hyperparathyroidism), and one patient had mixed uremic bone disease--predominantly hyperparathyroidism but some impairment of bone mineralization as well. As has recently been reported by others, the deferoxamine infusion test yielded unusual results in these patients. On the basis of our observations, we believe that an isolated measurement of BAC to determine whether aluminum-related osteomalacia is present has certain limitations. Aluminum-related bone disease can be accurately diagnosed only with use of bone histomorphometry. Elevated levels of immunoreactive parathyroid hormone may offer protection from the toxic effects of aluminum.

Aluminum-related osteomalacia: Relationship between hyperparathyroidism and osteoid seams width

Aluminum-related osteomalacia: Relationship between hyperparathyroidism and osteoid seams width

Aluminum-related osteomalacia contributes to the development of oral complications of primary hyperoxaluria

Aluminum-related osteomalacia contributes to the development of oral complications of primary hyperoxaluria

Histological healing of aluminum-related osteomalacia leads to multiple al lines in bone

Histological healing of aluminum-related osteomalacia leads to multiple al lines in bone