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.     

Aluminum-associated bone disease in chronic renal failure: high prevalence in a long-term dialysis population

Twenty-seven asymptomatic patients treated with hemodialysis longer than 8 years (mean 12.9 +/- 3.1 years) underwent bone biopsy to determine the prevalence of aluminum-associated bone disease. None had excess aluminum exposure from the dialysate. Ten patients (37%) had aluminum-associated bone disease as defined by a bone formation rate (BFR) below normal in the presence of stainable bone aluminum that covered more than 25% of the trabecular surface. The predominant type of bone histology in this group was the aplastic lesion characterized by low bone turnover, a decreased number of osteoblasts, and lack of excess unmineralized osteoid. Osteoblastic osteoid was highly correlated with stainable surface bone aluminum (r = -.82, p less than .001). Among the dynamic bone parameters, the double-tetracycline labeled surface was a more sensitive indicator of impaired bone function than was the bone apposition rate (BAR), since half of the patients with aluminum-associated bone disease had a normal BAR. In all of the biopsies the extent of double-labeled surfaces was inversely proportional to the amount of stainable aluminum on the bone surface (r = -.71, p less than .001), whereas stainable bone aluminum did not correlate with BAR. In seven of the patients with aluminum-associated bone disease, amino-terminal PTH levels were in the normal range while only one patient had a normal plasma mid-region PTH. PTH correlated directly with osteoblastic osteoid, BFR, and double-labeled surfaces. These results indicate that long-term oral aluminum intake in hemodialysis patients results in a high prevalence of aluminum-associated bone disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma insulin-like growth factors and bone formation in uremic hyperparathyroidism

Bone formation in uremia is considered to be regulated in part by parathyroid hormone (PTH). However, while low levels of immunoreactive PTH are usually associated with low rates of bone formation in uremia, elevated PTH levels do not always correlate with increased bone formation. In an attempt to identify other factors that may regulate bone formation in uremic patients, we measured plasma immunoreactive insulin-like growth factors (IGF-I and IGF-II) in 15 patients who did not have aluminum-associated reductions in bone formation. Plasma levels of IGF-I but not PTH, were significantly higher in patients with high rates of bone formation when compared to patients with low or normal bone formation (P less than 0.02). While the bone formation rate at the tissue level correlated significantly with plasma PTH (r = 0.53, P less than 0.05) and IGF-I (r = 0.67, P less than 0.01), only for plasma IGF-I were there significant correlations with bone apposition (r = 0.57, P less than 0.05) and bone formation rate at the BMU level (r = 0.62, P less than 0.02), parameters which reflect mineralization activity at the cellular level. Among the static histologic parameters, osteoblastic osteoid correlated only with plasma PTH (r = 0.76, P less than 0.001), while osteoclast number correlated with both PTH (r = 0.56, P less than 0.05) and IGF-I (r = 0.67, P less than 0.01). There were no correlations between IGF-II levels and bone histology. From these data we suggest that IGF-I may promote bone formation in uremic patients with hyperparathyroidism.(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.     

Bone histologic response to deferoxamine in aluminum-related bone disease

We have examined the changes in bone histology in 28 uremic patients after long-term treatment with the aluminum chelator, deferoxamine. Marked declines in stainable bone-surface aluminum were associated with increases in bone formation rate and osteoblastic osteoid following deferoxamine. The increased bone formation resulted from increases in bone apposition and length of double-tetracycline labels, the latter being highly correlated with the increase in osteoblastic osteoid (r = 0.85). While bone surface aluminum was highly correlated with bone formation rate (r = .69, p less than .001), bone aluminum content did not correlate with bone formation (r = 0.13) and was often elevated after treatment despite an improvement in bone histology. Patients who had undergone prior parathyroidectomy were less likely to have improved bone histology than those with intact parathyroid glands. We conclude that aluminum chelation therapy with deferoxamine is effective in ameliorating the bone histology of patients with chronic renal failure and bone aluminum accumulation, and that the change in stainable bone-surface aluminum is a more sensitive indicator than the change in bone aluminum content in assessing adequacy of chelation therapy. Patients who need deferoxamine treatment but have undergone a prior parathyroidectomy will probably require a more intensive treatment schedule than those who have intact parathyroid glands.     

Osteocalcin, iPTH, alkaline phosphatase and hand X-ray scores as predictive indices of histomorphometric parameters in renal osteodystrophy

To evaluate the relationship between hyperparathyroid bone X-ray lesion, biochemical parameters and bone histology in chronic renal failure, 59 patients (52 +/- 14.9 years; Crs 4.7 +/- 2.2 mg/dl, mean +/- SD) on conservative treatment and 103 (48 +/- 14 years) on hemodialysis (from 48.4 +/- 36.7 months) were studied. Right-hand X-ray was carried out for evaluation of the scores (0-3) of acroosteolysis (score A) and subperiosteal resorption (score B). Serum iPTH, osteocalcin and alkaline phosphatase (AP) were measured. In addition in a subset of 53 patients, 30 in predialysis and 23 in dialysis, a bone biopsy was performed for histomorphometry. In predialysis the scores A and B correlated with bone GLA protein (BGP) (p less than 0.01), AP (p less than 0.05) and osteoid surface (p less than 0.05) and 0.01 respectively). In hemodialysis the same level of significant correlation (p less than 0.001) was found between the scores and the three humoral parameters. Score A correlated with active osteoblastic surface and active resorption surface while score B correlated with active osteoblastic surface (p less than 0.01), osteoid surface and active resorption surface (p less than 0.05). Multiple regression analysis carried out to establish the predictive variables of bone histologic lesions (active resorption surface and active osteoblastic surface) singled out BGP in predialysis and AP and the two scores in dialysis. We conclude that serum BGP, as compared to PTH and AP, prevails as a valid marker of hyperparathyroid bone lesion in predialysis, while in dialysis it does not seem to add further information to that carried by other variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationships between calcium and phosphorus homeostasis, parathyroid hormone levels, bone aluminum, and bone histomorphometry in patients on maintenance hemodialysis

Serum biochemistry related to calcium and phosphorus homeostasis and parathyroid function was studied together with bone histomorphometry after double-labeling with tetracycline and staining for aluminum in 17 patients without symptoms of bone disease, treated with maintenance hemodialysis for at least 6 months. A close correlation was found between the serum level of parathyroid hormone (PTH) and bone resorption surfaces and bone formation rates, both at tissue and basic multicellular unit (BMU) levels. The patients could be divided into a high turnover group with a normal mineralization process and a low turnover group with markedly defective mineralization. The second group was further characterized by lower PTH and higher fractional aluminum-stained trabecular bone surfaces. For the whole patient material, the fractional aluminum-stained surfaces related inversely to tetracycline-labeled surfaces and to bone formation rates at both BMU and tissue levels, but not to the time on dialysis or to the cumulative ingested amount of aluminum hydroxide. The data provide evidence that PTH or PTH-related factors, besides activating bone remodeling, directly enhance bone formation in dialysis patients and that aluminum incorporation into bone is associated with a progressive disturbance of bone mineralization.     

Evidence for a toxic effect of aluminum on osteoblasts: a histomorphometric study in hemodialysis patients with aplastic bone disease

To evaluate the potential role of aluminum (Al) in a subset of dialysis patients with aplastic bone disease, we have studied tetracycline-labeled bone biopsies of 32 patients (22 males and 10 females, 45-73 years) on maintenance hemodialysis. Selection criteria included normal resorption surfaces (RS) and osteoid thickness. Eleven patients (Group I) had no stainable bone Al (Al-; 61.7 +/- 7.2 years) and 21 (Group II) had stainable bone Al (Al+; 57.7 +/- 6.8 years). Serum Al was normal to slightly elevated in Group I, but significantly higher in Group II (p less than 0.01). Al surfaces (AlS), undetectable in Group I, were 67.8 +/- 17.9% in Group II. Bone Al content (BAC) was much lower in Group I than in Group II (14.8 +/- 3.7 vs. 113.8 +/- 100.2 micrograms/g, p less than 0.01), but higher in Group I than in controls (p less than 0.05). Extensive thin osteoid seams were present in Group II. AlS was correlated with OS (r = 0.56, p less than 0.001) and OV (r = 0.48, p less than 0.01). Labeled surfaces were decreased in both groups. Labeled osteoid surfaces (TLS/OS) were below 2 SD of the mean control values in 96% of patients and calcification rate (CR) was depressed below 0.20 micros/day in 44% of patients. Bone formation rate (BFR) was strikingly depressed, values being below one SD of the mean control value in 92-100% of patients at both levels and below 2 SD of the mean in 82% of patients at BMU levels. Mineralization lag time (OMP) was markedly prolonged above 2 SD of controls in 89% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary hyperparathyroidism: changes in trabecular bone remodeling following surgical treatment--evaluated by histomorphometric methods

Iliac bone biopsies from 11 patients who underwent successful surgery for primary hyperparathyroidism were examined before and median 7 months after surgical treatment. Trabecular bone volume increased (p less than 0.05) and eroded (p less than 0.005) and osteoid covered surfaces decreased (p less than 0.005) in the postoperative period. Also, a decline in tetracycline labeled surfaces was noticed (p less than 0.02). Osteoid thickness, mineral appositional rate and mineralization lag time were unchanged. Bone formation rate at the level of the basic multicellular unit (BMU) was unaffected, but at the tissue level bone formation rate diminished (p less than 0.02). The surgical cure of primary hyperparathyroidism was found accompanied by a change in bone metabolism as the trabecular bone remodeling decreased from a high turnover to a low turnover state. The spongy bone mass increased after parathyroidectomy but the clinical significance of this finding was not clear.     

Serum aluminum levels as a reflection of renal osteodystrophy status and bone surface aluminum staining.

Twenty eight (14%) out of 196 patients in a regional dialysis population were found to have serum aluminum levels greater than or equal to 5 mumol/L or 135 micrograms/L; 21 consented to undergo a bone biopsy to identify the spectrum of renal osteodystrophy associated with this degree of hyperaluminemia. Both the Aluminon reagent and the acid solochrome azurine (ASA) stain were used to identify aluminum deposits. A control group of 13 patients with biochemical and histological evidence of severe secondary hyperparathyroidism was used to contrast the measured parameters of bone histology in the hyperaluminemic group. Al(OH)3 was used as the principal phosphate binder in all patients. In the hyperaluminemic group, 67% had either dialysis osteomalacia or aplastic bone lesions, and all except one aplastic lesion were positive for bone surface aluminum deposits by the Aluminon stain. The Aluminon stain was also positive in one of three cases of osteitis fibrosa and three of four mild lesions, whereas it was negative in all biopsies from the control group. However, the ASA stain was positive in all biopsies from the hyperaluminemic group and in 11 of 13 control biopsies from the patients with "pure" osteitis fibrosa. For all biopsy data from both groups, there were significant (P less than 0.01) negative correlations between the ASA-stained surface aluminum deposits and resorption indices (total eroded surface, r = -0.68; surface osteoclast counts, r = -0.53) and indices of bone formation (surface osteoblast counts, r = -0.61; mineral apposition rate, r = -0.63; bone formation rate, r = -0.69). These correlations were not significant for Aluminon-stained surface deposits with the exception of the bone formation indices, which had lower correlation coefficients (r = -0.44). These data suggest that hyperaluminemia greater than or equal to 5 mumol/L has a predictive value to identify impaired mineralization in dialysis patients that is high enough to affect clinical decision making. However, the more sensitive ASA stain identifies surface aluminum across the whole spectrum of renal osteodystrophy and is consistent with a toxic role for aluminum at any level of exposure.     

Elevated bone aluminum and suppressed parathyroid hormone levels in hypercalcemic dialysis patients

We studied 21 dialysis patients who became hypercalcemic without vitamin D or calcium therapy and compared them to 28 dialysis patients who were not hypercalcemic. In the hypercalcemic group, the mean ionized-calcium level was elevated compared to normal subjects (5.4 +/- 0.4 vs. 4.9 +/- 0.1; p less than 0.001), while the ionized-calcium level in the control dialysis patients was below normal (4.5 +/- 0.4 vs. 4.9 +/- 0.1; p less than 0.001). Bone biopsies were performed in all patients. Two thirds of the hypercalcemic patients had low-turnover osteodystrophy (LTO, predominantly osteomalacia), a fraction significantly higher than in the control dialysis patients (13/21 vs. 8/28, respectively; p less than 0.05). The hypercalcemic patients with LTO had markedly elevated surface bone aluminum (63 +/- 24% of all trabecular surfaces). In contrast, the nonhypercalcemic dialysis patients with LTO and all patients with osteitis fibrosa had minimal surface bone aluminum. Hypercalcemic patients with osteitis fibrosa had a significantly lower mean N-terminal parathyroid hormone (PTH) value than did nonhypercalcemic patients with osteitis fibrosa (149 +/- 81 vs. 278 +/- 135 pg/ml, respectively; p less than 0.005). Both mean values were markedly elevated in comparison with those obtained in normal subjects (16 +/- 5 pg/ml). In contrast, patients with LTO, irrespective of the calcium level, had mean PTH values that were not significantly different from those of normal subjects. A PTH level greater than 100 pg/ml was 95% sensitive and 87% specific for osteitis fibrosa, as demonstrated by histomorphometry in nonhypercalcemic dialysis patients. However, this level was only 62% sensitive and 77% specific for a diagnosis of osteitis fibrosa in hypercalcemic dialysis patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bone changes occurring early after cessation of ovarian function in beagle dogs: a histomorphometric study employing sequential biopsies

The beagle dog model has been established by our laboratory as a useful animal model to study bone loss after cessation of ovarian function. Previously we demonstrated bone loss associated with an osteoblastic insufficiency at 4 months after ovariohysterectomy (OHX). This study was designed to evaluate by four sequential monthly bone biopsies the development and course of the histologic bone abnormalities after OHX. We found cancellous bone volume, trabecular density, and wall thickness to be decreased (p less than 0.05) and trabecular separation increased (p less than 0.05) as early as 1 month after OHX. After 2 months, there was a decrease in mineralizing surface and mineral apposition rate (p less than 0.05). Volume and surface of osteoid were increased after 3 months (p less than 0.05), and there was an increase in the number of osteoblasts (p less than 0.01). No histologic signs of increased resorption were observed during the experiment. However, the findings of low bone volume with decreased trabecular density and increased separation without a change in trabecular plate thickness 4 weeks after OHX suggest that a dramatic increase in resorption must have taken place soon after OHX. These results point to an early phase of initiation of bone loss related to hyperresorption followed by a maintenance phase of low bone mass ascriblastic insufficiency. The events that stimulate the early initiating phase after cessation of ovarian function, the factors contributing to it, and the direct demonstration of hyperresorption await further studies.     

Alteration of noncollagenous bone matrix proteins in distal renal tubular acidosis

Our previous report on bone histomorphometry in patients with distal renal tubular acidosis (dRTA) revealed decreased bone formation rate (BFR) when compared to healthy subjects. The abnormality improved significantly after alkaline therapy. The modest increase in osteoblastic surface, after correction of metabolic acidosis, could not explain the striking improvement in bone formation, suggesting additional influence of metabolic acidosis on osteoblast function and/or bone matrix mineralization. Osteoblasts and, to a lesser extent, osteoclasts synthesize and secrete bone matrix including type I collagen and various noncollagenous proteins (NCPs). Substantial evidence suggested diverse functions of NCPs related to bone formation, resorption, and mineralization. Metabolic acidosis, through its effect on bone cells, may result in an alteration in the production of NCPs. Our study examined bone histomorphometry with detailed analysis on the mineralization parameters and NCPs expression within the bone matrix of patients with dRTA before and after treatment with alkaline. Seven dRTA patients underwent bone biopsy at their initial diagnosis and again 12 months after alkaline therapy. Bone mineral density (BMD) and bone histomorphometry were obtained at baseline and after the treatment. The expression of NCPs was examined by immunohistochemistry, quantitated by digital image analysis, and reported as a percentage of area of positive staining or mineralized trabecular bone area. Alkaline therapy normalized the low serum phosphate and PTH during acidosis. The reduction in BMD at baseline improved significantly by the treatment. Bone histomorphometry demonstrated the increase in osteoid surface and volume without significant alteration after acidosis correction. In comparison to the normal subjects, osteoid thickness was slightly but insignificantly elevated. Osteoblast and osteoclast populations and their activities were suppressed. The reduction in mineral apposition rate and adjusted apposition rate were observed in conjunction with the prolongation of mineralization lag time. Alkaline therapy improved the mineralization parameters considerably. In addition to the increase in BFR relative osteoblast number after acidosis correction, osteocalcin expression in the bone matrix increased significantly from 16.7% to 22.3%. Six of seven patients had decreased osteopontin expression. In conclusion, the abnormal bone remodeling in dRTA is characterized by low turnover bone disease with some degree of defective mineralization. Alteration of NCPs expression suggested the effect of metabolic acidosis on bone cells. Alkaline therapy increased bone mass through the restoration of bone mineral balance and, perhaps, improved osteoblast function.     

A randomized study on the effects of estrogen/gestagen or high dose oral calcium on trabecular bone remodeling in postmenopausal osteoporosis

Thirty-seven patients with postmenopausal crush fracture osteoporosis were randomized to oral cyclic estrogen/gestagen (n = 20) or oral calcium (2000 mg elemental calcium per day) (n = 17). Fourteen in each group completed 1 year of treatment. Iliac crest bone biopsies were obtained after intravital double labeling with tetracycline before and after treatment in 10 patients on estrogen/gestagen and 11 patients on calcium. In the estrogen/gestagen group the activation frequency in trabecular bone decreased from 0.52 + 0.11 (SEM) year-1 to 0.27 + 0.08 year-1 (p less than 0.01). No significant changes were found in resorption or formation periods. The osteoid surfaces and the mineralizing surfaces decreased (p less than 0.05), whereas the decrease in eroded surfaces was insignificant. Furthermore, no significant changes were observed in final resorption depth, wall thickness or bone balance per remodeling cycle. Serum alkaline phosphatase and renal hydroxyproline excretion decreased during treatment (p less than 0.002), whereas the lumbar bone mineral content (BMC) increased (p less than 0.01). In the calcium group the extent and thickness of osteoid surfaces decreased (p less than 0.05) without significant changes in activation frequency. Serum alkaline phosphatase and renal hydroxyproline excretion decreased during treatment (p less than 0.02). No significant changes were observed in lumbar BMC or the other histomorphometric parameters. The study supports that the positive effect of estrogen/gestagen on BMC can be explained by a reduction in the activation frequency of new remodeling cycles leading to a decreased remodeling space and an increase in mean bone age. There is no evidence of a positive balance per remodeling cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Optimal correction of acidosis changes progression of dialysis osteodystrophy

To investigate an eventual role of acidosis on hemodialysis osteodystrophy we prospectively studied 21 patients who were dialyzed with different amounts of bicarbonate in the dialysate for 18 months. According to the level of bone formation rate (BFR) on a prestudy bone biopsy, patients were split in two subgroups. Inside these two subgroups patients were randomly allocated to two therapeutics groups: 10 patients (group A) were dialyzed with the conventional amount of bicarbonate (33 +/- 2 mmol/liter) in the dialysate; the rest of the patients (group B, N = 11) had 7 to 15 mmol/liter sodium bicarbonate added to the dialysate to obtain 24 mEq predialysis bicarbonate plasma levels. An effective correction of acidosis was shown in group B by a higher predialysis plasma bicarbonate level (15.6 +/- 1 group A vs. 24.0 +/- 0.6 mEq/liter group B, P less than 0.005), which was reached three months after start of the study. Compared to the prestudy bone biopsy, osteoid and osteoblastic surfaces increased in group A but not in group B on the bone biopsies performed at the end of the study. Parathormone plasma level (iPTH), measured with an antiserum which cross reacts with the 44-68 region of PTH molecule, increased during the study in group A but not in group B. This finding suggested progression of secondary hyperparathyroidism (HPT) only in group A patients. Osteocalcin plasma values increased in both groups during the 18 months of the study. Consequently the two subgroups of patients formed on the basis of BFR level were evaluated separately.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bone remodeling rate and remodeling balance are not co-regulated in adulthood: implications for the use of activation frequency as an index of remodeling rate.

Use of activation frequency as a measure of remodeling rate assumes co-regulation of remodeling rate and remodeling balance. In iliac crest biopsy specimens from 57 healthy subjects 19-80 yr of age, no correlations were shown between these variables, an observation that challenges the use of activation frequency as an estimate of remodeling rate. INTRODUCTION: The histomorphometric derivation of activation frequency assumes that the remodeling rate is dependent on the duration of the remodeling cycle and the amount of bone formed in individual remodeling units. This implies that remodeling balance and remodeling rate are co-regulated. We tested this assumption in normal human adult cancellous bone. MATERIALS AND METHODS: Relationships between indices of bone formation at the basic multicellular unit (BMU) level (wall width and mineral apposition rate) and indices of remodeling rate (mineralizing perimeter and osteoid perimeter) were examined in iliac crest biopsies obtained from 57 healthy adults (24 men) 19-80 yr of age. RESULTS: Univariate analysis revealed a negative correlation between wall width and osteoid perimeter (r = -0.38; p = 0.0004), but there was no correlation between wall width and mineralizing perimeter or between mineral apposition rate and either mineralizing or osteoid perimeter. After adjustment for age and sex, the association between wall width and osteoid perimeter was no longer observed. Both wall width and mineral apposition rate correlated negatively with age (r = -0.75, p < 0.0001 and r = -0.27, p = 0.05, respectively). CONCLUSIONS: Our results indicate that remodeling balance and remodeling rate are not co-regulated in adult human bone. Activation frequency, as currently derived from histomorphometric variables, may therefore be unreliable as an indicator of remodeling rate.     

Parathyroid hormone and bone histology: response to hypocalcemia in osteitis fibrosa

The parathyroid hormone (PTH) response to hypocalcemia was studied in 18 hemodialysis patients with osteitis fibrosa, and the relationship with PTH and bone histology in 26 hemodialysis patients. Hypocalcemia was produced during hemodialysis by the use of a dialysate devoid of calcium. Both amino (N) (P less than 0.05) and carboxy (C) (P less than 0.005) terminal PTH attained maximum levels by 15 min despite only a minimal decline in plasma calcium. Throughout the remainder of the study, C and N-PTH levels remained elevated but did not increase despite a further decline in plasma calcium. Five patients increased both C and N-PTH to maximum or near maximum levels by the first sampling, although plasma calcium remained above 9 mg/dl. Basal C and N-PTH correlated with the maximum levels of each induced by hypocalcemia (P less than 0.005). Both basal N-PTH and the maximum change in C-PTH produced by hypocalcemia correlated with osteoblastic osteoid, active resorption, osteoclasts/mm2, and endosteal fibrosis (P less than 0.005). In conclusion, (1) a minimal decline in plasma calcium produces a maximum C and N-PTH response; (2) an altered PTH set point may be present in some hemodialysis patients; (3) the correlation between basal and maximally stimulated PTH levels suggests that basal PTH levels may reflect parathyroid gland mass; and (4) a correlation with basal and stimulated PTH and bone histology is present.     

Non-aluminic adynamic bone disease in non-dialyzed uremic patients: a new type of osteopathy due to overtreatment?

Adynamic bone disease, characterized by a low bone formation rate with normal or reduced amount of unmineralized osteoid, is supposed to be the consequence of aluminum intoxication in uremic patients. However, the emergence of adynamic bone disease has been recently reported in hemodialyzed patients in the total absence of aluminum overload. This study was aimed to assess whether such a histological pattern of adynamic bone disease was already present in uremic patients not yet on dialysis. Twenty-seven asymptomatic uremic patients (mean age +/- SD 43 +/- 10 years, mean creatinine clearance 19 +/- 3 ml/mm) were studied and bone biopsies were repeated in 16 of them after 18 +/- 10 months of treatment with oral calcium carbonate (1-3 g of elemental calcium/day) and calcidiol (21 +/- 14 micrograms/day). None of the patients received aluminum hydroxide, and the search for bone aluminum deposits was negative in all patients both before and after treatment. Two patients fulfilled the criteria of adynamic bone disease on their post-treatment biopsies. They originated from patients classified as having normal bone histology before treatment. Comparison with the other patients showed that they had comparable plasma C-terminal PTH but higher plasma creatinine than patients with normal bone histology and lower plasma C-terminal PTH than patients with osteitis fibrosa but comparable plasma creatinine. The plasma levels of 1,25(OH)2D reached values above normal after treatment in these two patients. It is suggested that adynamic bone disease not related to aluminum intoxication can develop in uremic patients independently of dialysis, and is favored by a relative hypoparathyroidism for the degree of renal failure, possibly induced by elevated plasma concentrations of calcitriol.     

Mean wall thickness and formation periods of trabecular bone packets in corticosteroid-induced osteoporosis

We have compared the mean wall thickness (MWT) and active formation periods (sigma f(A] of trabecular bone packets in iliac crest biopsies from 20 patients (7 male, 13 female) with corticosteroid-induced osteoporosis (CS-OP) and 20 age- and sex-matched controls. The trabecular bone volume (TBV) of the CS-OP patients (9.6% +/- 2.2% [SD]) was significantly reduced compared to controls (19.3% +/- 5.1%). The MWT of CS-OP patients (32.7 +/- 4.3 micron) was also significantly lower than the control value (48.0 +/- 6.2 micron). There was a positive correlation between MWT and TBV in both groups. The mineralization rate (M) of the CS-OP patients (0.54 +/- 0.25 micron/day) was within the normal range, and since there was no increase in osteoid seam thickness, so therefore was the osteoblastic appositional rate (OAR). The active formation period of trabecular bone packets (sigma f(A) = MWT/M) was significantly lower in the CS-OP patients (55.9 +/- 14.4 days) than in the control group (68.1 +/- 9.4 days). MWT and sigma f(A) both decreased with age in the control group, whereas in the CS-OP group they were independent of age. We conclude that corticosteroid therapy results in a reduction of the MWT of trabecular bone packets and, consequently, of TBV. In these patients, where the OAR was normal, the reduction in MWT was apparently caused by a shortening of the life-span of the active osteoblastic population at the basic multicellular unit (BMU) level.     

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.