Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study.

Increased bone turnover has been suggested as a potential risk factor for osteoporotic fractures. We investigated this hypothesis in a prospective cohort study performed on 7598 healthy women more than 75 years of age. One hundred and twenty-six women (mean years 82.5) who sustained a hip fracture during a mean 22-month follow-up were age-matched with three controls who did not fracture. Baseline samples were collected prior to fracture for the measurement of two markers of bone formation and three urinary markers of bone resorption: type I collagen cross-linked N- (NTX) or C-telopeptide (CTX) and free deoxypyridinoline (free D-Pyr). Elderly women had increased bone formation and resorption compared with healthy premenopausal women. Urinary excretion of CTX and free D-Pyr, but not other markers, was higher in patients with hip fracture than in age-matched controls (p = 0.02 and 0.005, respectively). CTX and free D-Pyr excretion above the upper limit of the premenopausal range was associated with an increased hip fracture risk with an odds ratio (95% confidence interval) of 2.2 (1.3-3.6) and 1.9 (1.1-3.2), respectively, while markers of formation were not. Increased bone resorption predicted hip fracture independently of bone mass, i.e., after adjustment for femoral neck bone mineral density (BMD) and independently of mobility status assessed by the gait speed. Women with both a femoral BMD value of 2.5 SD or more below the mean of young adults and either high CTX or high free D-Pyr levels were at greater risk of hip fracture, with an odds ratio of 4.8 and 4.1, respectively, than those with only low BMD or high bone resorption. Elderly women are characterized by increased bone turnover, and some markers of bone resorption predict the subsequent risk of hip fracture independently of hip BMD. Combining the measurement of BMD and bone resorption may be useful to improve the assessment of the risk of hip fracture in elderly women.

Relationship between bone fluoride content and histological evidence of calcification defects in osteoporotic women treated long term with sodium fluoride.

Fluoride treatment is used to increase bone formation and cancellous bone mass in patients suffering from postmenopausal osteoporosis with vertebral fractures. Patients submitted to similar therapeutic protocols have shown various histological responses to the treatment, some developing calcification defects and others not. In fact, the bone histological response to fluoride salts depends on the cumulative uptake of fluoride by bone. To clarify the relationship between the presence of calcification defects (identified by the presence of mottled bone and linear formation defects) and the bone fluoride content, a retrospective study was performed on 29 women with type 1 osteoporosis and treated for several months (11-24) with sodium fluoride (50 mg/day), calcium and vitamin D. Bone fluoride content always significantly increased after treatment, but it was significantly higher in patients showing calcification defects than in those having no defects. These differences between the two groups of patients were not due to differences in clinical details (no significant differences concerning age, duration of treatment, total amount of fluoride ingested, renal function) or in their bone remodelling activity. Thus, it may be hypothesized that the high bone fluoride uptake is due to different individual responses from one patient to another concerning the bioavailability of the same dose of fluoride. This is difficult to predict, except by testing the individual bioavailability of the compound to be used in each patient before starting long-term treatment.

Serum osteocalcin is increased in patients with osteomalacia: correlations with biochemical and histomorphometric findings.

The synthesis of osteocalcin or bone gla protein by osteoblasts is markedly stimulated by 1,25-(OH)2D, a key hormone in the regulation of bone mineralization. The circulating levels of osteocalcin have been shown to reflect both the osteoid matrix production and the formation rate of mineralized bone in several metabolic bone diseases (osteoporosis, thyrotoxicosis, primary hyperparathyroidism) in which both mechanisms are tightly coupled because of the absence of mineralization defect. In this study, we measured in 12 patients (7 women, 5 men, 56 +/- 15 yr old) with untreated osteomalacia serum osteocalcin and vitamin D metabolites (25OHD and 1,25-(OH)2D). The results were correlated with biochemical and histomorphometric assessment of bone remodeling. Osteomalacia was due to vitamin D deficiency (5 cases), to vitamin D malabsorption (6 cases), and to hypophosphataemia in 1 case. When compared to control values, serum osteocalcin was increased in patients with osteomalacia (7.4 +/- 4 vs. 3.7 +/- 1.3 ng/mL; P less than 0.001) and was positively correlated with serum alkaline phosphatase (r = 0.65; P = 0.03) and negatively with 25 OHD (r = -0.61; P = 0.04). Serum osteocalcin was not correlated with 1,25-(OH)2D [r = -0.45; not significant (NS)] even after exclusion of the patient with hypophosphataemia. Serum osteocalcin was positively correlated with the osteoid volume and osteoid perimeter (r = 0.71 and 0.69 respectively; P less than 0.01) but not with any of the tetracycline-based parameter of bone mineralization at the tissue level (r ranging from -0.41 to +0.42, NS). Serum 25 OHD, but not 1,25-(OH)2D, was positively correlated with the mineralization rate (r = 0.59; P less than 0.05 and r = 0.54; NS). We conclude that in patients with osteomalacia, a condition which is characterized by an increased osteoid accumulation due to a decreased mineralization rate, the increased level of serum osteocalcin reflects the increased osteoid synthesis but not the mineralization defect. In this disease, serum osteocalcin is inversely correlated to the severity of vitamin D deficiency reflected by serum 25 OHD, but not to the serum levels of 1,25-(OH)2D.

Effects of ossein-hydroxyapatite compound on ewe bone remodeling: biochemical and histomorphometric study.

Ossein-hydroxyapatite compound (OHC) is a protein-mineral complex derived from bovine bone. Its effects on bone remodeling were studied in old ewes which have seasonal variations in bone remodeling. Seven animals received 200 mg OHC/kg b.w./day for 90 days from July to September. The control group consisted of 7 untreated animals followed for the same period of time. OHC was administered through a fistula into the fourth stomach. A significant decrease of bone histomorphometric parameter values was noted in controls at the end of the experiment, due to seasonal variations: the cancellous eroded perimeter decreased by 45%, the osteoblastic perimeter by 60% and the bone formation rate at the cell level by 20%. In contrast, in the treated-group, these parameters tended to increase or did not change. In conclusion, counteracting the significant seasonal reduction of bone remodeling in ewes, OHC seems able to stimulate directly or indirectly bone metabolism, especially when osteoblast activity is reduced and may partly prevent the seasonal reduction of bone turnover.

Dose effects on ewe bone remodeling of short-term sodium fluoride administration--a histomorphometric and biochemical study.

The early effects of two doses of sodium fluoride (NaF) on bone remodeling was studied in 14 ewes divided into two groups. Group I received orally 1 mg NaF/kg/day and group II received a five-fold greater dose. No calcium supplement was given. Transiliac bone biopsies and blood samples were taken before treatment (T0) and after 45 (T45) days of treatment. Bone fluoride content significantly increased in group II. In both groups, a significant decrease of serum calcium and phosphorus, and a slight but nonsignificant augmentation in serum parathyroid hormone were noted. Osteoid perimeter and area were significantly increased. The osteoid width significantly increased in both groups, but was twice higher in group II than I. At T45, the osteoblast perimeter increased in both groups. Osteoid perimeter was significantly correlated with serum osteocalcin values (r = 0.74; p less than 0.001) and bone fluoride content (r = 0.64; p less than 0.01). The bone formation rate at tissue level tended to increase in both groups. Concerning the apposition rate, a decrease was noted which was 1.5-fold higher in group II than in I. The increased formation period resulted from a prolonged inactive period in group II. These results point out a stimulatory effect of fluoride on the birth rate of osteoblasts. However, fluoride prolonged the lifespan of osteoblasts that had reduced activity.

Skeletal fluorosis: histomorphometric findings.

Histomorphometric analysis of undecalcified sections was performed in transiliac biopsy cores taken from 29 patients (16 men, 13 women, aged 51 +/- 17 years) suffering from skeletal fluorosis due to chronic exposure to fluoride. The origin of the exposure, known in 20 patients, was either by water (endemic or sporadic), or industrial, or in a few cases iatrogenic. Measured on calcified bone using a specific ion electrode, bone fluoride content was significantly high in each specimen (mean +/- SD: 0.79 +/- 0.36% of bone ash) as compared to control values (less than 0.10%). The radiologically evident osteosclerosis observed in each patient was confirmed by the significant increase of cancellous bone volume (40.1 +/- 11.2 vs. 19.0 +/- 2.8% in controls, p less than 0.0001). There were significant increases in cortical width (1292 +/- 395 vs. 934 +/- 173 microns, p less than 0.0001) and porosity (14.4 +/- 6.4 vs. 6.5 +/- 1.7%, p less than 0.002), but without reduction of cortical bone mass. Osteoid parameters were significantly increased in fluorotic patients. The increase in cancellous osteoid perimeter was almost threefold greater than that noted in cancellous eroded perimeter. The fluorotic group had a greater number of osteoblasts than controls, with a very high proportion of flat osteoblasts. In 15 patients doubly labeled with tetracycline, the mineral apposition rate was significantly decreased, while mineralization lag time significantly increased. Bone formation rate and adjusted apposition rate were significantly decreased in skeletal fluorosis. Cancellous wall width was normal in fluorosis but the formation period and active formation period were significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of bone and kidney in parathyroid hormone-related peptide-induced hypercalcemia in rats.

A protein responsible for the biochemical syndrome similar to primary hyperparathyroidism associated with certain tumors has been recently characterized and its effects at the level of bone and kidney reported. However, the relative role of tubular reabsorption of calcium (Ca) and bone resorption in the pathogenesis of hypercalcemia induced by this factor is still debated. We investigated the effects of a synthetic amino-terminal fragment of parathyroid hormone-related protein [PTHrP-(1-34)] administered chronically by intraperitoneal osmotic minipumps in thyroparathyroidectomized (TPTX) rats. Clearance studies performed on day 6 of treatment after a 24 h fast revealed an increase in renal tubular reabsorption of Ca and a decrease in renal tubular reabsorption of phosphate (Pi), accompanied by an increase in cAMP excretion. PTHrP-(1-34) (90 pmol/h) stimulated bone resorption as evaluated by an increment in fasting urinary Ca excretion. Although the bone resorption inhibitor aminopropylidene diphosphonate fully corrected urinary Ca excretion and reduced plasma Ca from 3.04 +/- 0.07 to 2.44 +/- 0.21 mM (p less than 0.05), this latter value remained considerably higher than in TPTX control rats (1.54 +/- 0.12 mM, p less than 0.01). In contrast, when the agent WR-2721, which is known to decrease the renal tubular reabsorption of Ca by a PTH-independent mechanism, was given, a further drop in plasma Ca and an increase in urinary Ca excretion were observed. These findings are similar to those found in animals implanted with the hypercalcemic Leydig cell tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Skeletal fluorosis: histomorphometric analysis of bone changes and bone fluoride content in 29 patients.

Bone fluoride content (BFC) was measured and histomorphometric analysis of undecalcified sections was performed in transiliac biopsy cores from 29 patients (16 men, 13 women, aged 51 +/- 17 years) suffering from skeletal fluorosis due to chronic exposure to fluoride. The origin of the exposure, known in 20 patients, was either hydric (endemic or sporadic) or industrial, or in a few cases iatrogenic. Measured on calcined bone using a specific ion electrode, BFC was significantly high in each specimen (mean +/- SD; 0.79 +/- 0.36% on bone ash). The radiologically evident osteosclerosis observed in each patient was confirmed by a significant increase in cancellous bone volume (40.1 +/- 11.2% vs. 19.0 +/- 2.8% in controls, p less than 0.0001). There were significant increases in cortical width (1292 +/- 395 mcm vs. 934 +/- 173 mcm, p less than 0.0001) and porosity (14.4 +/- 6.4% vs. 6.5 +/- 1.7%, p less than 0.002), but without reduction of cortical bone mass. Cancellous osteoid volume and perimeter, as well as width of osteoid seams, were significantly increased in fluorotic patients. The increase in cancellous osteoid perimeter was almost three-fold greater than that noted in cancellous eroded perimeter. In 15 patients doubly labeled with tetracycline, the mineral apposition rate was significantly decreased, mineralization lag time was significantly increased. The fluorotic group had a greater number of osteoblasts than controls with a very high proportion of flat osteoblasts. The ultrastructural characteristics reflecting the activity of the bone cells were clearly visible on electron microscopy. Bone formation rate and adjusted apposition rate were significantly decreased in skeletal fluorosis. On stained sections and microradiographs, bone tissue showed typical modifications for skeletal fluorosis (linear formation defects, mottled bone). The volume of cancellous interstitial mineralization defects and the proportion of mottled periosteocytic lacunae were markedly increased in skeletal fluorosis. These two parameters were significantly correlated together but neither of these was significantly correlated with BFC. Renal function did not significantly influence the changes in BFC and histomorphometry of fluorotic patients. Skeletal fluorosis is thus characterized by an unbalanced coupling in favor of bone formation, and a great number of osteoblasts with a high proportion of flat osteoblasts.(ABSTRACT TRUNCATED AT 400 WORDS)

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)

Beneficial effects of aminohexane diphosphonate in patients with Paget's disease of bone resistant to sodium etidronate.

Clinical and biochemical resistance to sodium etidronate therapy is not rare in patients with severe Paget's disease of bone, especially after several courses of treatment. Sixteen patients with Paget's disease of bone and well-documented resistance to sodium etidronate were treated with a new diphosphonate, aminohexane diphosphonate, given orally for three months at a daily dose of 400 mg. These patients comprised a selected population of patients with very active disease, as shown by a mean 20-fold increase of serum alkaline phosphatase levels before aminohexane diphosphonate therapy. Aminohexane diphosphonate induced a striking reduction of serum alkaline phosphatase and urinary hydroxyproline levels sustained for up to 18 months after withdrawal of treatment. Two patients had a relapse 14 to 16 months after treatment, and received a second course of aminohexane diphosphonate with the same efficacy. This was accompanied by marked clinical improvement, a reduction of the radioisotope uptake by pagetic bones, and radiologic healing of osteolytic lesions in some cases. Iliac crest biopsy specimens taken after tetracycline double-labeling showed no impairment of bone mineralization. No clinical or biochemical adverse effects have been observed.

Deferoxamine-induced bone changes in haemodialysis patients: a histomorphometric study.

1. The histological effects of deferoxamine therapy were assessed on transiliac bone biopsies taken after double tetracycline labelling from 16 uraemic patients undergoing chronic haemodialysis, all having aluminium deposits in bone. Eight patients had osteomalacia, five had an "aplastic" bone lesion and three a high bone turnover with a marked increase in osteoid volume. 2. Deferoxamine was administered intravenously once a week at doses ranging from 1 to 6 g for a mean duration of 7.6 +/- 3.3 (SD) months. 3. Deferoxamine therapy was associated with significant reductions in stainable aluminium deposits, osteoid volume, osteoid surfaces and thickness index of osteoid seams. The osteoblastic osteoid surfaces as well as the bone formation rates also increased significantly. 4. A rise in resorption parameters and in serum parathyroid hormone levels was observed in patients with osteomalacia. The percentage reductions in stainable aluminium and in osteoid volume were correlated with the degree of hyperparathyroidism. 5. These data show that deferoxamine therapy reduces stainable bone aluminium and improves bone mineralization in low turnover osteomalacia and that the presence of hyperparathyroidism is associated with an increased response to deferoxamine therapy.

Intravenous disodium etidronate therapy in Paget's disease of bone and hypercalcemia of malignancy. Effects on biochemical parameters and bone histomorphometry.

Nineteen patients with Paget's disease and four patients with hypercalcemia of malignancy underwent hypocalcemic therapy with etidronate disodium (etidronate) administered intravenously. The dosage for patients with Paget's disease was 4.3 mg/kg/day, infused on each of seven consecutive days. Nine of the 19 patients also received oral etidronate 5 mg/kg/day for three months after administration of intravenous therapy. Etidronate administered orally sustained the decreases in urinary hydroxyproline produced by the infusions, whereas levels returned to pretreatment values in most patients receiving only the intravenously administered drug. Serum alkaline phosphatase levels were not reduced in the 10 patients receiving only intravenously administered etidronate, but they declined by approximately 50 percent in the nine patients who received the additional orally administered etidronate. Transiliac-crest bone biopsy specimens obtained three months after intravenous therapy revealed a regular lamellar structure, compared with the characteristic woven pattern of pagetic bone. In all four patients with hypercalcemia of malignancy, normocalcemia was achieved by the 10th day of treatment using a dosage of 4.3 mg/kg/day. Oral etidronate therapy was beneficial in maintaining normocalcemia.

Serum bone Gla-protein in renal osteodystrophy: comparison with bone histomorphometry.

Serum bone Gla-protein (S-BGP) and other serum biochemical parameters, including alkaline phosphatase (S-AP) and immunoreactive PTH (S-iPTH), were measured in 42 patients undergoing chronic hemodialysis. Each patient also had a tetracycline-labeled transiliac bone biopsy, allowing correlations between the biochemical and trabecular bone histomorphometric parameters, S-BGP was markedly increased [64.0 +/- 74.8 (+/- SD) vs. 6.2 +/- 2.2 ng/ml in normal subjects] significantly correlated with S-AP (r = 0.53) and S-iPTH (r = 0.55) levels. S-BGP was significantly higher in the 14 patients with high turnover renal osteodystrophy (HT-ROD; S-BGP, 138.5 +/- 90.8 ng/ml) than in the 28 patients with low turnover (LT-ROD; S-BGP, 26.8 +/- 14.8 ng/ml). S-BGP was significantly correlated with the cellular parameters of bone resorption and formation (r = 0.57-0.69) and with the dynamic parameters of bone formation (r = 0.62-0.82). The extent of stainable bone aluminum was significantly negatively correlated with S-BGP (r = -0.51) and serum iPTH (r = -0.33), but not with S-AP. S-BGP measurement allowed better discrimination between LT-ROD and HT-ROD groups than did S-AP measurement. However, in the patients with LT-ROD, S-BGP did not discriminate between patients with or without osteomalacia. We conclude that S-BGP is a valuable marker for evaluating bone remodeling and, more specifically, the bone formation rate at the tissue level in hemodialyzed patients.

[Osteocalcin (or bone gla-protein), a new biological marker for studying bone pathology]. / L'ostéocalcine (ou gla-protéine osseuse), nouveau marqueur biologique pour l'étude de la pathologie osseuse.

Osteocalcin, also called bone gla-protein, is a bone matrix protein synthetized specifically by osteoblasts. It circulates in blood where it can be assayed by the radioimmune method. We measured osteocalcin serum levels in 169 adult controls and 161 patients with different disseminated or localized bone diseases. The normal concentration of 6.2 +/- 0.2 ng/ml increases significantly with age. Serum osteocalcin levels are considerably increased in renal osteodystrophy (114 +/- 23 ng/ml) and to a lesser degree in primary hyperparathyroidism (15.9 +/- 2.8 ng/ml) and Paget's disease (11.4 +/- 0.9 ng/ml), all diseases characterized by increased bone turnover. High levels are also encountered in osteomalacia (9.7 +/- 0.9 ng/ml). Conversely, serum osteocalcin levels are significantly decreased in patients under long-term corticosteroid therapy (4.3 +/- 0.5 ng/ml); they remain normal in patients with bone myeloma and bone metastases under treatment. Finally, osteocalcin is normal in patients with osteoporosis, but its level reflects that of bone turnover as evaluated by iliac bone biopsy. The circulating osteocalcin therefore is the first specific and sensitive marker for bone turnover. Serum osteocalcin measurements make it possible to evaluate the osteoblastic bone formation without biopsy and should provide information on the effectiveness of drugs acting on the bone-forming process.

Serum bone gamma carboxyglutamic acid-containing protein in primary hyperparathyroidism and in malignant hypercalcemia. Comparison with bone histomorphometry.

Serum bone gamma-carboxyglutamic acid-containing (Gla) protein (sBGP), a sensitive and specific marker of bone turnover, was measured in 25 patients with primary hyperparathyroidism and in 24 patients with bone metastases with or without hypercalcemia. Despite similar levels of hypercalcemia, sBGP was increased in primary hyperparathyroidism (14.2 +/- 9.6 ng/ml, P less than 0.001), was decreased in malignant hypercalcemia (3.1 +/- 2.8 ng/ml, P less than 0.001), and was normal in patients with bone metastases without hypercalcemia (6.6 +/- 2.7 ng/ml). In primary hyperparathyroidism, sBGP was correlated with serum immuno-reactive parathyroid hormone (r = 0.90), calcium (r = 0.73), and with the adenoma weight (r = 0.79). After parathyroidectomy, sBGP slowly returned to normal values within 2-6 mo, suggesting that sBGP reflects increased bone turnover rather than a direct effect of parathyroid hormone on BGP synthesis at the cell level. An iliac crest biopsy was performed in 11 patients with primary hyperparathyroidism and in 9 cancer patients in a noninvaded area. sBGP was significantly correlated with all parameters reflecting bone formation but not with bone resorption. Patients with bone metastases were analyzed according to the presence or the absence of hypercalcemia. In contrast to normocalcemic patients who had normal sBGP, hypercalcemic patients had decreased sBGP (P less than 0.001) and a lower bone formation at the cellular level (P less than 0.05). Thus, biochemical and histological data suggest that an unknown humoral factor might be responsible for this uncoupling between increased resorption and decreased formation. This uncoupling, rather than local release of calcium by the metastatic process, might be responsible for hypercalcemia in patients with bone metastases.

[Histomorphometric profile of bone fluorosis induced by prolonged ingestion of Vichy Saint-Yorre water. Comparison with bone fluorine levels]. / Profil histomorphométrique de la fluorose osseuse induite par l'ingestion prolongée d'eau de Vichy Saint-Yorre. Comparaison avec le taux de fluor osseux.

Nine transiliac bone biopsies from 7 patients with skeletal fluorosis due to prolonged ingestion of often high quantities of Vichy Saint-Yorre water were analyzed. Four of these patients also suffered from a chronic renal failure. A histomorphometric study was possible in 8 out of the 9 biopsies. The measurement of bone fluoride content, and a microradiographic examination, were performed on all bone samples. The radiologically evident osteosclerosis observed in each patient was confirmed by the significant increase of trabecular bone volume. Furthermore, the osteoid surfaces were very extended but the thickness of osteoid seams was normal in 6 out of 8 cases. Two biopsies demonstrated a morphological evidence of osteomalacia with abnormally thick osteoid seams. Calcification rate, measured in one of these 2 cases after tetracycline double labeling, was extremely low (less than 0.20 micron/d). The bone fluoride content was significantly high in each specimen (greater than 0.40 bone ash%) and correlated with relative osteoid volume (r' = 0.91) and thickness index of osteoid seams (r' = 0.83). Histologically, bone tissue showed modifications classically reported in the various types of skeletal fluorosis (formation defects, mottled bone with mottled periosteocytic lacunae). In conclusion, the prolonged administration of Vichy Saint-Yorre water containing 8.5 mg of fluoride ion per liter, provokes a skeletal fluorosis. This intoxication appeared very quickly if the patient suffered from an even mild renal failure. Once again, it is shown that a disturbed renal function predisposes to an excessive retention of fluoride.

[Desferrioxamine treatment of osteomalacia caused by aluminum poisoning]. / Traitement par la desferrioxamine de l'ostéomalacie par intoxication á l'aluminium.

Three haemodialyzed chronic renal failure patients with histologically proven osteomalacia due to aluminium toxicity were treated with repeated injections of desferrioxamine, a potent chelator of aluminium. The drug, in doses of 3 or 6 g, was administered intravenously once a week for 5 to 11 months, at the end of a dialysis session. Treatment was well tolerated. Dramatic clinical improvement was observed, with rapid regression of pain and functional impairment. There was a 65% increase in alkaline phosphatase and a rise of immunoreactive parathyroid hormone (terminal C fragment). Healing of fractures was confirmed by radiology, and a second bone biopsy in the 3 patients after double tetracycline labelling showed regression of morphological and dynamic signs of osteomalacia, considerable reduction in stainable aluminium deposits and strong increase in bone remodelling compatible with the development of hyperparathyroidism. It is concluded that a moderate dose of desferrioxamine administered once a week is effective against osteomalacia due to aluminium toxicity.

High bone turnover associated with an aluminum-induced impairment of bone mineralization.

A hemodialyzed patient showing x-ray and biochemical evidence of apparently pure severe hyperparathyroidism underwent a tetracycline-labeled transiliac bone biopsy. The bone biopsy not only confirmed the hyperparathyroid bone lesions but also revealed an impairment of bone mineralization induced by aluminum. This was demonstrated by a reduction of double-labeled osteoid surfaces, a significant increase in the osteoid seam thickness, and the presence of extensive aluminum deposits in bone. The planned parathyroidectomy was postponed, and deferoxamine (DFO) therapy, 2 g once a week, was initiated. A second bone biopsy, taken 6 months later, showed recovery of normal bone mineralization but the persistence of hyperparathyroid bone lesions. This was associated with a considerable reduction in the extent of aluminum deposits on trabecular bone surfaces. This observation shows that severe and apparently pure hyperparathyroidism can be associated with an impairment of bone mineralization induced by aluminum. This suggests that bone mineralization and aluminum overload should be evaluated in dialyzed patients who are being considered for parathyroidectomy.