Aluminum administration in the rat separately affects the osteoblast and bone mineralization

Aluminum administration in the experimental animal results in osteomalacia as characterized by osteoid accumulation and decreased mineralization. Previous in vivo and in vitro studies have indicated that either aluminum directly inhibits mineralization or is toxic to the osteoblast. In the present study, PTH was continuously infused in rats with aluminum-induced osteomalacia to evaluate whether aluminum administration decreased mineralization without a concomitant decrease in osteoblasts. Four groups of rats were studied: chronic renal failure (CRF); CRF + aluminum (AL); CRF + PTH; and CRF + PTH + AL. Rats were sacrificed 5 and 12 days after aluminum or diluent administration; in the PTH groups, bovine PTH (1-34) was administered at 2 units/h via a subcutaneously implanted Alzet pump. Aluminum administration decreased osteoblast surface, increased osteoid accumulation, and produced a cessation of bone formation. The infusion of PTH alone increased osteoblast surface and bone formation. The simultaneous administration of aluminum and PTH resulted in an osteoblast surface intermediate between aluminum and PTH alone; however, despite a PTH-induced restoration of osteoblast surface, bone formation did not increase. These findings indicate (1) aluminum is toxic to osteoblasts and also directly inhibits mineralization even when osteoblasts are not decreased; (2) PTH is capable of increasing osteoblasts even in the presence of aluminum; and (3) despite a PTH-induced increase in osteoblast surface, mineralization of osteoid was not improved.     

Differential diagnosis between secondary hyperparathyroidism and aluminum intoxication in uremic patients: usefulness of 99mTc-pyrophosphate bone scintigraphy

Forty-one patients in chronic end-stage renal failure and 4 patients with a functioning kidney transplant presented with spontaneous hypercalcemia or intolerance to vitamin D3 sterols and/or oral calcium supplements. Bone iliac crest biopsy with aluminum staining and Tc-pyrophosphate bone scintigraphy with determination of Fogelman score were performed in all cases. Two patients had aluminum-induced osteomalacia (AL O). Thirty-eight biopsies showed renal osteodystrophy (secondary hyperparathyroidism or various combinations of osteitis fibrosa and osteomalacia): 19 with positive staining for aluminum (RO + AL) and 19 without aluminum deposits (RO). The series also comprised 2 cases of pure osteomalacia (OM), 2 cases of osteoporosis (OP), and 1 case of osteoporosis with aluminum accumulation (OP + AL). Mean Fogelman score in RO patients (9.1 +/- 0.3) was significantly higher than in all other categories (5.9 +/- 0.5 for RO + AL, and scores ranging from 0 to 8 in the last 7 patients, p less than 0.01). Patients with massive aluminum accumulation in bone (greater than 75% of the total trabecular surface) showed no or very low uptake of the isotope by the skeleton. Fogelman scores of 9 or higher were always associated with histological secondary hyperparathyroidism. 99mTc-pyrophosphate bone scintigraphy is helpful to distinguish aluminum intoxication from secondary hyperparathyroidism in uremic patients.     

Dose-dependent effects of strontium on bone of chronic renal failure rats

BACKGROUND: We previously reported on increased bone strontium (Sr) 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 (CRF) rat model. METHODS: In the present study we investigated whether the effect of Sr on bone was related to dosage. Four groups of CRF rats were studied: a control group (control-CFR; N=6) not receiving strontium and three groups of animals loaded orally with Sr during 18 weeks by adding the element as the SrCl2. H20 compound to the drinking water at concentrations of 0.03 g/100mL (Sr-30; N=6), 0.075 g/100mL (Sr-75; N=6), or 0.15 g/100mL (Sr-150; N=6) respectively. A fifth group consisting of seven animals with intact renal function (control-NRF), not receiving Sr served as controls for the effect of CRF on bone histology. RESULTS: As compared to the control-NRF and control-CRF groups, Sr administration resulted in a dose-dependent increase in bone and serum Sr levels. No difference in body weight and biochemical serum and urinary parameters [i.e., calcium (Ca), phosphorus (P), and creatinine] was noted between the various CRF groups. At sacrifice, intact parathyroid hormone (iPTH) levels of CRF groups were significantly (P < 0.05) higher than the values measured in the control-NRF group indicating the development of hyperparathyroidism secondary to the installation of the CRF. This is further supported by the differences in bone histomorphometry between the control-CRF and control-NRF animals, which, respectively, showed an increased amount of osteoid (mean +/- SEM 3.4 +/- 1.2% vs. 0.37 +/- 0.14%, P < 0.05) in combination with a distinct osteoblastic activity (35 +/- 11% vs. <2%, P < 0.05) and an increased bone formation rate [(BFR), 677 +/- 177 microm 2/mm2/day vs. 130 +/- 50 microm 2/mm2/day, P < 0.05]. Bone surface area and erodic perimeter did not differ between the various study groups. In the Sr-30 group, Sr loading went along with a dramatic reduction of the BFR as indicated by the total absence of double tetracyclin labels and osteoblastic activity, which in the presence of a low to normal amount of osteoid (2.7 +/- 1.9%) points to the development of the adynamic type of renal osteodystrophy. Interestingly, compared to the control-CRF group, histodynamic and histologic parameters of the Sr-75 group did not differ significantly and a substantial osteoblastic activity (7.6 +/- 4.0%) was seen also. In the Sr-150 group, the various osteoid parameters were significantly (P < 0.05) increased vs. all other groups and were accompanied by a reduced BFR and mineral apposition rate (MAR) and an increased mineralization lag time (MLT), indicating a mineralization defect and the development of osteomalacia. CONCLUSIONS: Our findings indicate that the role of Sr in the development of bone lesions in renal failure is complex and that, depending on the dose, the element may act via multiple pathways.     

Thyroparathyroidectomy modifies the skeletal response to aluminum loading in the rat

Diminished parathyroid hormone (PTH) secretion may contribute to the accumulation of aluminum (Al) in bone and to impaired bone formation in Al-related bone disease. Therefore, intact (AL, N = 9) and thyroparathyroidectomized (TPTX-AL, N = 9) rats were given intraperitoneal injections of Al, 2 mg/day, for 42 days; intact control (C, N = 11) and TPTX control (TPTX-C, N = 9) animals received i.p. injections of vehicle only. Quantitative bone histology and measurements of mineralized bone formation (Rbf) using double tetracycline labeling were done for cortical and for trabecular bone; trabecular bone aluminum content (BA) was determined by histochemical methods. BA did not differ between AL and TPTX-AL, 33 +/- 13% versus 39 +/- 14%, and Rbf decreased similarly from control values in both Al-treated groups. In contrast, osteoid production was impaired to a greater extent in TPTX-AL than in AL. Thus, osteoid area and osteoid seam width were each lower in TPTX-AL than in TPTX-C; these values did not differ between AL and C. TPTX can aggravate Al induced reductions in osteoid synthesis, and low serum PTH levels may contribute to the pathogenesis of aplastic bone. However, reductions in Rbf during Al loading are not mediated by PTH.     

Effect of aluminum and parathyroid hormone on osteoblasts and bone mineralization in chronic renal failure

Bone aluminum, quantitative bone histology, and plasma parathyroid hormone (PTH) were compared in 29 patients undergoing chronic hemodialysis. Histologic techniques included double tetracycline labeling and histochemical identification of osteoclasts and osteoblasts. Bone aluminum was measured chemically by flameless atomic absorption spectrophotometry, and histochemically. When measured chemically, the bone aluminum was 67 +/- 46 (SD) mg/kg dry weight (normal 2.4 +/- 1.2 mg/kg); histochemically, aluminum was present at 2.9 +/- 4.4% of trabecular surface. The biochemical and histochemical results agreed well (r = 0.80, P less than 0.001). No double tetracycline labels were seen at the mineralization front where aluminum was deposited, indicating cessation of mineralization at these sites. The osteoblast surface correlated positively with plasma PTH (r = 0.67, P less than 0.001) and negatively with bone aluminum level (r = -0.42, P less than 0.05). Multiple linear regression showed a correlation of aluminum with osteoblasts additional to that of PTH, consistent with a direct effect of aluminum in depressing osteoblast numbers. Though a relationship between PTH and chemically determined bone aluminum level could not be demonstrated, there was a negative correlation between osteoclast count and aluminum, and the nine patients with severe hyperparathyroid bone disease had lower chemically determined aluminum levels than the other patients. These results suggest that aluminum (a) directly inhibits mineralization, (b) is associated with decreased PTH activity and hence osteoblast numbers, and (c) directly reduces osteoblast numbers. In addition to inducing severe, resistant osteomalacia, aluminum appears to contribute to the mild osteomalacia commonly seen in renal failure, characterized by extensive thin osteoid and low tetracycline and osteoblast surfaces.     

Stainable aluminum and not aluminum content reflects bone histology in dialyzed patients

Quantitative evaluation of stainable bone aluminum and measurement of bone aluminum content were done in 55 patients on chronic maintenance dialysis. All patients underwent bone biopsies. Histomorphometry of static and dynamic parameters of bone structure, bone formation and resorption, and quantitation of stainable bone aluminum at the osteoid-bone interface were performed. In addition, bone aluminum content was measured by atomic absorption spectrophotometry. Bone aluminum content was elevated in all patients (81 +/- 9.6 vs. 18 +/- 6 micrograms/g dry wt) and stainable aluminum was found in 47% of them. All patients with predominant low-turnover osteomalacia or adynamic bone disease displayed stainable bone aluminum. In contrast, stainable bone aluminum was not present in individuals with predominant-hyperparathyroid bone disease. Patients with stainable aluminum had lower bone mass (P less than 0.05), higher volume and surface of lamellar osteoid (P less than 0.01), less volume and surface of woven osteoid (P less than 0.05 and P less than 0.01), lower osteoblastic and osteoclastic indices (P less than 0.01), less doubly labelled osteoid seams, lower mineral apposition rate and lower bone formation rates (P less than 0.05 to P less than 0.01). Stainable aluminum correlated with volume of lamellar osteoid and cellular parameters of bone formation and resorption, mineral apposition rate, and bone formation rates (P less than 0.05 to P less than 0.001). In contrast, bone aluminum content correlated with volume of lamellar osteoid only (P less than 0.001). These findings indicate that stainable aluminum at the mineralization front and not aluminum content of bone reflects the histopathologic changes found in bone of dialyzed patients.     

The evolution of osteomalacia in the rat with acute aluminum toxicity

Aluminum toxicity is the presumed cause of aluminum-associated osteomalacia. In animal models, osteomalacia has been produced after a prolonged course of aluminum. In the present study, rats with renal failure received 20 mg intraperitoneal aluminum during a 2 day period. This model allows sequential observations in the development of osteomalacia. Rats were sacrificed and studied 5, 12, 25, and 40 days after aluminum administration. No differences were observed in serum calcium, phosphorus, or creatinine as a consequence of aluminum administration. Compared with control rats, parathyroid hormone was decreased at 12 and 25 days. A direct correlation was present between plasma and bone aluminum at 12 days (r = 0.92, p less than 0.01), 25 days (r = 0.85, p less than 0.005), and 40 days (r = 0.88, p less than 0.001) but not 5 days after aluminum administration. Plasma aluminum peaked at 5 days (727 +/- 89 micrograms/liter, mean +/- SEM) and bone aluminum at 40 days (273 +/- 40 micrograms/g). Aluminum had profound effect on bone histology. At 5 days there was a decrease in osteoblast surface and osteoid surface; at 12 days osteoblast surface and osteoid surface returned to normal but osteoclast surface decreased. Subsequently there was a progressive increase in osteoid surface and osteoid volume. Bone formation rate measured at 12, 25, and 40 days was decreased at these intervals. In conclusion, (1) high plasma aluminum may be directly toxic to the osteoblast; (2) progressive osteoid accumulation is secondary to matrix (osteoid) deposition, which exceeds the depressed bone formation rate; (3) the progressive decrease in plasma aluminum and increase in bone aluminum suggest that bone has a high affinity for aluminum but may have a relatively slow rate of uptake at any given time; (4) aluminum may directly decrease parathyroid hormone; (5) the correlation between plasma and bone aluminum suggest an exchange is present; and (6) aluminum toxicity may independently affect the osteoblast and bone mineralization.     

Reversal of aluminum-related bone disease after substituting calcium carbonate for aluminum hydroxide

Aluminum-related osteodystrophy, a crippling disease in patients with renal failure, can develop from the long-term ingestion of aluminum hydroxide gels. We present a diabetic patient treated with continuous ambulatory peritoneal dialysis (CAPD) who developed markedly elevated plasma aluminum levels but no musculoskeletal symptoms. Bone biopsy revealed features of the aplastic form of aluminum-related disease with significant aluminum staining, decreased osteoblastic osteoid, and decreased bone formation by double tetracycline labeling, but no excess accumulation of unmineralized osteoid. Aluminum hydroxide gels were discontinued and the patient received calcium carbonate to control hyperphosphatemia; 9 months later, a bone biopsy showed marked improvement of the aluminum-related bone disease, and at 2 to 10 months, plasma aluminum had decreased from 208.7 +/- 10.3 (SE) to 55.7 +/- 3.9 micrograms/L.     

The effects of discontinuation of aluminum exposure on aluminum-induced osteomalacia

Studies in patients on dialysis have shown that aluminum (Al) accumulation in bone plays a major role in the pathogenesis of osteomalacia. It has been suggested that deferoxamine (DFO) may be beneficial in the treatment of aluminum-induced osteomalacia. The present studies were performed in four groups of uremic rats to determine if DFO and/or discontinuation of Al administration have an effect on bone histomorphometry and blood chemistries. The groups were: 1) uremic control 2) aluminum (0.75 to 1.0 mg/rat i.p., five times a week for twelve weeks): 3) aluminum + DFO, after twelve weeks Al was discontinued and the rats received DFO (75 mg/rat two times a week for nine weeks); 4) aluminum + time, after twelve weeks Al was discontinued and the rats were sacrificed after nine weeks. High levels of Al in serum and bone and low levels of PTH were seen in rats receiving Al. Bone histology revealed Al at the mineralization front, abnormal tetracycline uptake, and an increase in osteoid. DFO treatment did not significantly change the level of Al in bone, however both DFO treatment and discontinuation of Al reversed towards normal the above described lesions. In conclusion, these studies suggest that DFO and/or discontinuation of Al administration to rats with approximately 30% of renal function greatly improve aluminum-induced osteomalacia.     

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)     

Chronic metabolic acidosis in azotemic rats on a high-phosphate diet halts the progression of renal disease

BACKGROUND: Hyperphosphatemia and metabolic acidosis are general features of advanced chronic renal failure (RF), and each may affect mineral metabolism. The goal of the present study was to evaluate the effect of chronic metabolic acidosis on the development of hyperparathyroidism and bone disease in normal and azotemic rats on a high-phosphate diet. Our assumption that the two groups of azotemic rats (acid-loaded vs. non-acid-loaded) would have the same degree of renal failure at the end of the study proved to be incorrect. METHODS: Four groups of rats receiving a high-phosphate (1.2%), normal-calcium (0.6%) diet for 30 days were studied: (1) normal (N); (2) normal + acid (N + Ac) in which 1.5% ammonium chloride (NH4Cl) was added to the drinking water to induce acidosis; (3) RF, 5/6 nephrectomized rats; and (4) RF + acid (RF + Ac) in which 0.75% NH4Cl was added to the drinking water of 5/6 nephrectomized rats to induce acidosis. RESULTS: At sacrifice, the arterial pH and serum bicarbonate were lowest in the RF + Ac group and were intermediate in the N + Ac group. Serum creatinine (0.76 +/- 0.08 vs. 1.15 +/- 0.08 mg/dL), blood urea nitrogen (52 +/- 8 vs. 86 +/- 13 mg/dL), parathyroid hormone (PTH; 180 +/- 50 vs. 484 +/- 51 pg/mL), and serum phosphate (7.46 +/- 0.60 vs. 12.87 +/- 1.4 mg/dL) values were less (P < 0.05), and serum calcium (9.00 +/- 0.28 vs. 7.75 +/- 0.28 mg/dL) values were greater (P < 0.05) in the RF + Ac group than in the RF group. The fractional excretion of phosphate (FEP) was greater (P < 0.05) in the two azotemic groups than in the two nonazotemic groups. In the azotemic groups, the FEP was similar even though PTH and serum phosphate values were less in the RF + Ac than in the RF group. NH4Cl-induced acidosis produced hypercalciuria in the N + Ac and RF + Ac groups. When acid-loaded (N + Ac and RF + Ac) and non-acid-loaded (N and RF) rats were combined as separate groups, serum phosphate and PTH values were less for a similarly elevated serum creatinine value in acid-loaded than in non-acid-loaded rats. Finally, the osteoblast surface was less in the N + Ac group than in the other groups. However, in the acid-loaded azotemic group (RF + Ac), the osteoblast surface was not reduced. CONCLUSIONS: The presence of chronic metabolic acidosis in 5/6 nephrectomized rats on a high-phosphate diet (1) protected against the progression of RF, (2) enhanced the renal clearance of phosphate, (3) resulted in a lesser degree of hyperparathyroidism, and (4) did not reduce the osteoblast surface. The combination of metabolic acidosis and phosphate loading may protect against the progression of RF and possibly bone disease because the harmful effects of acidosis and phosphate loading may be counterbalanced.     

Sigmoidal relationship between calcitonin and calcium: studies in normal, parathyroidectomized, and azotemic rats.

Calcitonin secretion is stimulated by acute hypercalcemia. Furthermore, in the rat, the calcemic response to parathyroid hormone (PTH) is decreased by calcitonin stimulation. However, in renal failure, it is not known if an increase in the serum calcium concentration within the physiologic range of serum calcium stimulates calcitonin and whether the increased calcitonin decreases the calcemic response to PTH. In the present study, four groups of pair-fed rats were evaluated: normals (N); parathyroidectomy (PTX); and two groups with renal failure (RF)--basal serum calcium less than 8.5 mg/dl (RFa) and basal serum calcium greater than 8.5 mg/dl (RFb). Hypocalcemia was induced by parathyroidectomy or in the RFa group, by a high phosphate diet. Increases in the serum calcium were produced by a 48 hour infusion of rat 1-34 PTH. In the RFa and PTX groups, stimulation of calcitonin was observed as the serum calcium increased from hypocalcemia to normal levels of calcium (P less than 0.01). In all four groups, increasing the serum calcium from normal levels to hypercalcemia increased the serum calcitonin level (P less than 0.05). The relationship between serum calcitonin and calcium was best expressed as a sigmoidal curve. In the two groups with basal hypocalcemia, PTX and RFa, the calcitonin-calcium curve was shifted to the left of the N and RFb groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Parathyroid hormone response to hypocalcemia in hemodialysis patients with osteomalacia

The parathyroid hormone response to hypocalcemia was investigated in hemodialysis patients with osteomalacia and compared to those with osteitis fibrosa. Hypocalcemia was induced during hemodialysis by employing a dialysate devoid of calcium. Patients with osteomalacia had a blunted maximum amino terminal parathyroid hormone response (+/- SD) (0.39 +/- 0.33 vs. 0.87 +/- 0.53 ng/ml, P less than 0.05) and maximum carboxy terminal parathyroid hormone response (+/- SD) (0.36 +/- 0.20 vs. 0.84 +/- 0.47, P less than 0.02) to hypocalcemia. The decline in plasma calcium was greater in patients with osteomalacia at 90 (P less than 0.05), 120 (P less than 0.01), and 150 min (P less than 0.01). In osteomalacia patients the surface density of histologically detectable trabecular bone aluminum correlated directly with the percent relative osteoid volume (P less than 0.005) and inversely with the maximum amino terminal parathyroid hormone response to hypocalcemia (P less than 0.025). These results suggest that hemodialysis patients with osteomalacia have diminished secretion of parathyroid hormone and a decreased ability to restore plasma calcium homeostasis during hypocalcemia.     

Calcemic response to parathyroid hormone in renal failure: role of calcitriol and the effect of parathyroidectomy.

Hyperparathyroidism due to renal failure begins in the early stages of renal insufficiency and is in part secondary to skeletal resistance to the calcemic action of parathyroid hormone (PTH). Factors which have been reported to reduce the calcemic response to PTH include: decreased calcitriol levels, hyperphosphatemia and down regulation of PTH receptors in bone. While hyperphosphatemia may directly decrease the calcemic response to PTH, it may also act indirectly by a suppression of calcitriol synthesis. In this study, the effect of calcitriol on the calcemic response to PTH was evaluated in normal rats and in rats with moderate and advanced renal failure. To determine the combined effect of calcitriol and phosphorus on the calcemic response to PTH, rats receiving calcitriol were fed either a high (1.0%) or low (0.2%) phosphorus diet during a 48-hour PTH infusion. In advanced renal failure, calcitriol administration increased the calcemic response to PTH independent of the dietary phosphorus intake. During ingestion of a low phosphorus diet, a 48 hour PTH infusion resulted in a serum calcium level of 13.7 +/- 0.5 and 12.1 +/- 0.2 mg/dl (P less than 0.02) with and without calcitriol administration, respectively. In normal rats and in rats with moderate renal failure, calcitriol administration improved the calcemic response only during a high phosphorus intake. After a 48-hour PTH infusion in normal rats, the serum calcium levels with and without calcitriol were 16.1 +/- 0.9 and 14.8 +/- 0.6 mg/dl, P less than 0.01 respectively; in rats with moderate renal failure, calcitriol administration increased serum calcium, 13.2 +/- 0.5 versus 11.2 +/- 0.4 mg/dl, P less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)     

Parenteral aluminum administration in the dog: II. Induction of osteomalacia and effect on vitamin D metabolism

There is an association between bone aluminum (Al) accumulation and dialysis-associated osteomalacia (OM). To study whether Al is pathogenic in OM, quantitative bone histomorphometry was done in six dogs before (Bx 1) and after (Bx 2) 3 to 5 weeks of intravenous Al administration (1 mg Al /kg/day). Bone Al was determined by histochemical and chemical methods. The percent osteoid rose from 2.8 +/- 0.8 to 7.0 +/- 4.3% (mean +/- SD), P less than 0.05, and osteoid width increased from 5.7 +/- 0.6 to 8.0 +/- 1.2 mu, P less than 0.01, after Al. Bone Al rose from 1.3 +/- 1.6 to 94.0 +/- 19.0 mg/kg after Al, and the severity of OM, expressed as either percent forming surface or percent osteoid, correlated with bone Al measured histochemically and expressed as either percent surface or percent area of trabecular bone staining for Al (r = 0.85 - 0.90, P less than 0.01). Poor tetracycline uptake (six dogs), which indicates impaired mineralization, and little or no separation of tetracycline labels (four dogs) were noted at Bx 2; thus, bone apposition and formation rates were below the limits of detection. Resorptive surface did not change but trabecular volume, expressed as percent of tissue volume, fell from 22.1 +/- 3.0 to 17.1 +/- 1.4%, P less than 0.05. Serum levels of 1,25(OH)2D fell from 26.8 +/- 9.1 to 4.5 +/- 5.5 pg/ml after 17 days of Al; serum 25(OH)D levels were unchanged. These data indicate that Al can cause OM and that its severity correlates with the bone Al content.2 +     

Impairment of bone formation with aluminum and ferric nitrilotriacetate complexes

Summary The deleterious effects of aluminum(Al) and iron(Fe) on bone formation were studied in the presence of nitrilotriacetate (NTA) as a chelator. Both Al-NTA (1.0–1.5 mg Al/kg/day, n=12)- and ferric nitrilotriacetate (Fe-NTA) (2.0 mg/kg/day, n=4)—treated Wistar rats showed renal insufficiency blood urea nitrogen [BUN] levels of 25±8.8−20±0.7 compared to 12±0.7–11±0.4 mg/dl), osteomalacia with a relative osteoid volume of 31.5±5.6−13.2±2.4 compared to 4.6±1.8−0.83±0.12%, and bone growth retardation (3.1±0−3.0±0.2 compared to 3.4±0−3.3±0.1 cm) in 24 control rats. Dietary vitamin E(VE) supplementation prevented the Fe-NTA-induced impairment, but not the Al-NTA toxicity. Aluminum was deposited at the interface between osteoid and mineralized bone, while Fe was deposited in the osteoblasts and osteoclasts. There seems to be a positive correlation between hypophosphatemia and osteomalacia but carboxy-terminal parathyroid hormone (C-PTH) and calcium (Ca) levels in the serum were not related to the degree of osteomalacia. Administration of Al-NTA results in more bone Al deposition than that of aluminum chloride (AlCl₃) (450±40 compared to 211±18 mg/kg fat-free dry weight). The Fe-NTA bone change is related to VE-preventable cellular injury, being consistent with the notion that Fe-NTA toxicity is caused by lipid peroxidation. Al-NTA can be used as an animal model of renal osteodystrophy. Osteodystrophy by Al in chronic renal failure may be mediated by the intrinsic chelator or chelating substance(s) retained in the body fluid due to renal insufficiency.     

Morphine pharmacokinetics in renal failure

The effect of chronic renal failure (RF) on the pharmacokinetics of morphine was studied in nine patients with end-stage RF, aged 58 +/- 8 yr (SD), and in seven control patients, aged 58 +/- 15 yr, undergoing peripheral surgery under general anesthesia. All patients received 0.2 mg X kg-1 as an intravenous bolus injection. Blood samples were collected over a 36 h period, and plasma concentrations were measured using a specific radioimmunoassay method. Unchanged morphine could be identified for only 12 h in all patients. The mean plasma concentrations of unchanged morphine were similar in the two groups, except in the first sample (5 min) where it was higher (P less than 0.05) in RF group. Patients with RF had a significantly smaller (P less than 0.05) central compartment (0.3 +/- 0.2 l X kg-1 versus 0.8 +/- 0.4 l X kg-1) than in the controls. Volume of distribution at steady state was also significantly (P less than 0.05) decreased in RF patients (2.8 +/- 1.0 l X kg-1) versus 3.7 +/- 1.2 l X kg-1 in the normal patients. The total apparent volume of distribution, the elimination half-life, and the plasma clearance were similar in the two groups. Identical peak levels of morphine metabolites were observed in the two groups, but plasma concentration of morphine metabolites was undetectable after 12 h in the control group and remained at a high level of 82 +/- 49 ng X ml-1 at 24 h and 83 +/- 57 ng X ml-1 at 36 h in RF patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bone mineral density and histology in distal renal tubular acidosis

BACKGROUND: Chronic metabolic acidosis in distal renal tubular acidosis (RTA) has been implicated in the pathogenesis of enhanced bone resorption and osteopenia, resulting in a loss of bone mineral content. However, histomorphometric and bone densitometric studies of patients who suffered from long-standing distal RTA have rarely been done. METHODS: A cross-sectional study to determine the alterations of bone mineral density (BMD) and histology was done in 14 nonazotemic RTA patients (11 females and 3 males) who had never received alkaline therapy before enrolling into this study. The mean age was 32.7 +/- 11.9 years. BMD measurements and transiliac bone biopsy were done in all patients. Blood chemistries, intact parathyroid hormone level, and a 24-hour urine collection for the determination of urinary calcium, phosphate, sodium, and potassium were obtained from the RTA patients at the time of bone biopsy. Data from 28 age-, sex-, and body mass index-matched, normal controls who were residents in the same area were also obtained. RESULTS: Urinary excretion of calcium was 2.05 +/- 1.59 mmol/day. No patient had hypercalciuria. The serum intact parathyroid hormone level was 15.92 +/- 8.48 pg/mL. RTA patients had lower BMD in most areas when compared with normal controls. There were two patients who suffered from a pathologic fracture at the femur. Bone histomorphometry from RTA patients shows a significantly decreased bone formation rate (0.02 +/- 0.02 vs. 0.07 +/- 0.045 microm(3)/microm(2)/day, P < 0.05), not significantly decreased osteoblastic surface (0.78 +/- 1.03% vs. 2.6 +/- 1.1%) and osteoclastic surface (0.05 +/- 0.03 vs. 0.13 +/- 0.23%), but significantly increased osteoid surface (31.47 +/- 24.52 vs. 5.79 +/- 4.39%, P < 0.05) and osteoid volume (2.95 +/- 3.09 vs. 0.92 +/- 1.05%, P < 0.05) when compared with those of normal controls. There was no difference in osteoid thickness (10.65 +/- 6.10 vs. 8.69 +/- 2.14 microm). Only one distal RTA patient who had a marked increase in osteoid thickness justified the diagnosis of osteomalacia. CONCLUSIONS: This study demonstrates that low bone mass is common in distal RTA patients. Chronic metabolic acidosis results in suppression of bone formation and resorption, which in turn may contribute to the development of low bone mass in distal RTA patients. Although minor elevations in osteoid surface and osteoid volume are found among distal RTA patients, overt osteomalacia is not the predominant bone lesion.     

Increased bone aluminum deposition after subtotal parathyroidectomy in dialyzed patients

Ten dialyzed patients underwent a systematic bone biopsy before and 19 +/- 9 months after subtotal parathyroidectomy (PTX). At the end of the follow-up period all the patients, except two, who complained of proximal myalgia, were asymptomatic. Compared to the bone biopsy specimen obtained prior surgery, decreased bone formation without mineralization impairment was observed after PTX. Despite an average decrease in aluminum gels intake after PTX, an increase in stained aluminum was observed (0.69 +/- 0.79 versus 1.20 +/- 0.95 mm/mm2, P less than 0.050). Aluminum accumulation depended on the pre-PTX bone aluminum load: pre- and post-PTX bone aluminum loads were correlated (r = 0.78, P less than 0.01). Bone aluminum accumulation was not related to the amount of aluminum gel intake after PTX; however, only two patients free of both bone aluminum deposit prior to PTX and aluminum gel intake after PTX had no stainable aluminum on the second bone biopsy after PTX. The only patient who had no decrease in bone formation after PTX had no increase in bone aluminum. Assuming that the patients had no aluminum deposit prior to dialysis, we measured the rate of bone aluminum accumulation. It rose from 0.11 +/- 0.09 mm/mm2/year prior to PTX to 0.40 +/- 0.25 mm/mm2/year after PTX (P less than 0.05) in the six patients who were maintained on phosphate binders and who had a decrease in bone formation after PTX. These six patients had unchanged aluminum gel intake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of parathyroidectomy on bone formation and mineralization in hemodialyzed patients

Undecalcified sections of doubly tetracycline-labeled transiliac bone biopsy specimens obtained from ten hemodialyzed patients before and 10 to 16 months after parathyroidectomy (PTX) were analyzed. Before parathyroidectomy (total PTX with autotransplant in six patients and subtotal PTX in four patients), all the patients demonstrated histological evidence of hyperparathyroidism with increased resorption parameters. A high bone formation rate (BFR) was noted in all patients but one who had both an increase in the osteoid seam thickness and a low calcification rate characteristic of osteomalacia. A significant correlation was found between immunoreactive parathyroid hormone (iPTH) levels and BFR at the tissue and at the basic multicellular unit (BMU) levels. Parathyroidectomy was associated with a dramatic drop in resorption surfaces and osteoclast number as well as in bone formation rate at the tissue, BMU, and cell-levels. After PTX, the bone formation rate at the tissue level was low or in the lower range of normal values in six patients. The thickness index of osteoid seams was significantly reduced and no evidence of osteomalacia was present even in the six patients showing bone aluminum deposits after PTX. One of the three patients, who had an iPTH level within the normal range after PTX, showed an osteoid excess associated with a low bone formation rate. These date demonstrate that increased PTH secretion is an important factor of bone formation in dialyzed patients and that excessive reduction of the PTH secretion leads to an inactive bone.