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PubMed1970

Urinary polypeptides related to collagen synthesis.

Of the total urinary hydroxyproline in normal subjects and those with skeletal disorders, between 4 and 20% was nondialyzable. In some patients with Paget's disease of bone, hyperparathyroidism with osteitis fibrosa, hyperphosphatasia, and extensive fibrous dysplasia the total urinary hydroxyproline was sufficiently high to permit purification of this polypeptide hydroxyproline by gel filtration and ion exchange chromatography. The partially purified polypeptides had molecular weights between 4500 and 10,000 and amino acid compositions and physical properties resembling those of gelatin. The polypeptide fractions also contained neutral sugar and glucosamine. These fragments had been shown to be susceptible to cleavage by purified bacterial collagenase suggesting the presence of the sequence-Pro-X-Gly-Pro-Y-. After administration of proline-(14)C to patients with Paget's disease hydroxyproline-(14)C was excreted in the urine. The hydroxyproline-(14)C specific activity reached a peak in 2-4 hr and declined rapidly. The specific activity of the polypeptide (retentate) portion was severalfold greater than that of the raw urine and diffusate. When the labeled urines were subjected to gel filtration the hydroxyproline-(14)C fractions of highest molecular weight which were eluted first from the columns had the highest specific activities. Exposure of the hydroxyproline-(14)C-containing polypeptides to bacterial collagenase rendered them dialyzable. Four patients with hyperparathyroidism and osteitis fibrosa were studied before and after removal of a parathyroid adenoma, a period of transition from a predominance of bone collagen resorption to one of relatively increased bone collagen synthesis. The total urinary hydroxyproline fell rapidly after operation whereas the ratio of the polypeptide fraction to the total rose three- to fourfold. The results of these studies suggest that the urinary polypeptides represent fragments of collagen related to collagen synthesis. Changes in the ratio of these peptides to total hydroxyproline in the urine may serve as an index of new bone formation in patients with skeletal disorders.

Adenoma↗

PubMed1994

Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy.

Intermittent calcitriol therapy is commonly used to treat secondary hyperparathyroidism in patients undergoing regular dialysis, but there is little available information about the histologic response of bone to this form of therapy. Accordingly, 14 children and adolescents with biopsy-proven secondary hyperparathyroidism were treated with intermittent oral or intraperitoneal doses of calcitriol for 12 months. Biochemical indices of mineral metabolism including serum intact PTH levels were measured monthly throughout the study, and bone biopsies were repeated at the end of treatment. Before treatment, 11 patients had osteitis fibrosa and three had mild lesions of secondary hyperparathyroidism. Histologic improvement was seen in 12 of 14 patients, and osteitis fibrosa resolved in 10 of 11 cases. Bone formation decreased in all patients during intermittent calcitriol therapy, falling from 861 +/- 380 to 150 +/- 170 microns2/mm2/day, P < 0.001. Bone formation decreased to normal in six patients, but six patients developed adynamic lesions of bone with subnormal bone formation rates. Serum PTH and alkaline phosphatase levels declined in those who developed adynamic bone, but values remained elevated in patients with normal rates of bone formation at follow-up evaluation. Neither the mean dose of calcitriol nor the average dose per kilogram body weight differed in patients with adynamic lesions. Thus, adynamic renal osteodystrophy develops in a substantial number of patients during intermittent calcitriol therapy. Although declining serum PTH and alkaline phosphatase levels suggest the development of the adynamic lesion, bone formation decreases in some patients despite persistently high serum PTH levels. Calcitriol may directly suppress osteoblastic activity in patients with secondary hyperparathyroidism when given in large doses to patients undergoing peritoneal dialysis.

Adolescent↗

PubMed1989

Disappearance of aluminic bone disease in a long term asymptomatic dialysis population restricting A1(OH)3 intake: emergence of an idiopathic adynamic bone disease not related to aluminum.

In dialysis centers using reverse osmosis-treated water but not restricting A1(OH)3 administration, a high prevalence of histological aluminum bone disease has been reported. To assess whether this is also the case in our center where A1(OH)3 intake has always been restricted and even completely given up after 1980 thanks to high doses of CaCO3, we reviewed 42 bone biopsies performed between 1975 and 1985 in patients dialyzed for a mean duration of 56 months. Seventeen of these patients had been dialyzed before 1978 with softened water moderately contamined by aluminum, 15 had always been dialyzed with reverse osmosis-treated water and 10 had been exclusively treated by hemofiltration. The prevalence of aluminum bone disease in the whole population was 9.5% (4 patients) and consisted only of adynamic bone disease, osteomalacia being totally absent. When the patients dialyzed with aluminum-contaminated water were excluded as well as 1 diabetic patient who had taken A1(OH)3 for 1.5 years the prevalence of aluminum bone disease was null in this population. When the whole population is considered the prevalence of the other types of bone disease was 76% for osteitis fibrosa and 14.5% for a non-aluminic adynamic bone disease (6 cases). These latter cases differed from the osteitis fibrosa group only by a relative hypoparathyroidism not explained by higher plasma concentrations and higher oral cumulative doses of calcium, magnesium and aluminum or by lower plasma concentrations of phosphate and bicarbonate. None had previous parathyroidectomy, one had an unsuccessful transplantation and one was diabetic. Iron overload was excluded by negative Perls staining.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Symptomatic hypercalcemia in a diabetic patient undergoing continuous ambulatory peritoneal dialysis: value of bone biopsy in the diagnosis and management.

An elderly man with diabetes mellitus and end-stage renal disease managed with continuous ambulatory peritoneal dialysis (CAPD) was hospitalized with peripheral vascular insufficiency; he developed hypercalcemia and became mentally obtunded. Lowering dialysate Ca from 3.5 mEq/L to 2.5 mEq/L, stopping calcium acetate, and ultimately hemodialysis with calcium-free dialysate did not lead to reversal of the hypercalcemia or improvement of his symptoms. The intact parathyroid hormone PTH level was 187 pg/mL, a value rarely associated with significant osteitis fibrosa. A search for other causes of hypercalcemia was unrevealing, and a iliac crest bone biopsy was done. The latter showed osteitis fibrosa, and the patient underwent parathyroidectomy. The hypercalcemia reversed quickly, and his mental symptoms slowly improved. The discussion reviews the probable causes of hypercalcemia in diabetic patient undergoing CAPD with 3.5 mEq/L dialysate calcium and using calcium-containing phosphate binders, with hyperparathyroidism certainly not the usual cause. The reason for the occurrence of significant hyperparathyroidism in the face of only modest elevation of PTH is considered. The value of bone biopsy in resolution of this problem is apparent.

Aged↗

PubMed2006

Direct maxacalcitol injection into hyperplastic parathyroids improves skeletal changes in secondary hyperparathyroidism.

Direct maxacalcitol (OCT) injection into a parathyroid gland (PTG) ameliorates several important etiologic factors of resistance to medical treatments for secondary hyperparathyroidism (s-HPT): the upregulations of vitamin D receptor (VDR) and Ca-sensing receptor (CaSR) in PTGs and the regression of PTG hyperplasia by the induction of apoptosis. In this study, we evaluated the bone histomorphology on the basis of maintaining these effects in advanced s-HPT. Five/six nephrectomized Sprague-Dawley rats were fed a high-phosphorus and low-calcium diet for 8 weeks. These rats were divided into four treatment groups: (1) basic uremic (at the baseline), (2) direct OCT single injection into PTGs (DI-OCT) followed by OCT intravenous administration for 4 weeks (IV-OCT), (3) direct vehicle injection and IV-OCT, and (4) no treatment for an additional 4 weeks. The effects of these treatments on serum intact-parathyroid hormone (PTH) level, PTG weight, VDR and CaSR expression levels in PTGs, and bone histomorphometric parameters were investigated. In the DI-OCT+IV-OCT group, the significant decrease in serum intact-PTH level was maintained by the following IV-OCT. A significant decrease in PTG weight and the upregulations of VDR and CaSR expression levels in PTGs were also observed. Bone histomorphometric analysis showed significant improvements in osteitis fibrosa in both cancellous and cortical bones. However, these findings were not observed in the other groups. These results suggest that osteitis fibrosa caused by advanced s-HPT can be successfully reversed by a control of PTH at an appropriate level through the improvement of PTG hyperplasia as induced by DI-OCT+IV-OCT.

Animals↗

PubMed1986

Controlled trial of calcitriol in hemodialysis patients.

We report on a 5-year, prospective, double-blind trial of 1,25 dihydroxycholecalciferol (calcitriol) versus placebo in 76 hemodialysis patients without biochemical or radiological evidence of bone disease. Calcitriol, 1 microgram daily, regularly induced hypercalcemia. Doses of 0.25 microgram daily or less proved satisfactory in most patients. During calcitriol treatment, plasma calcium concentration was significantly higher and serum parathyroid hormone concentration significantly lower than on placebo. There was no difference in the rates of development or of progression of vascular calcification in the two groups. Significantly more patients on placebo (17 vs. 6, p less than 0.05) developed a sustained elevation of plasma alkaline phosphatase concentration. Calcitriol appeared to protect against the development of histological evidence of osteitis fibrosa but not of osteomalacia, but accumulation of aluminum in bone occurred during the study. We conclude that calcitriol delays and may prevent the development of osteitis fibrosa in patients receiving regular hemodialysis and may reasonably be prescribed routinely in hemodialysis patients without biochemical or radiological abnormality, unless there is a substantial prospect of early renal transplantation.

Adolescent↗

PubMed2004

Leontiasis ossea in a patient with hyperparathyroidism secondary to chronic renal failure.

Osteitis fibrosa describes the bone changes seen in renal osteodystrophy secondary to longstanding hyperparathyroidism. We report a 19-year-old man with longstanding chronic renal failure with a severe form of osteitis fibrosa affecting the jaws and other maxillofacial bones causing bizarre facial and dental deformity in a patient-uraemic leontiasis ossea.

Adult↗

PubMed1978

Hemodialysis bone disease: correlation between clinical, histologic, and other findings.

This paper explores in patients with dialysis osteodystrophy the relationship between clinical features and histological, radiological, and biochemical findings. Eighty-five patients treated by hemodialysis for more than 6 months were studied. The following conclusions were drawn: 1) Bone pain in patients on regular hemodialysis is usually a symptom of developing osteomalacia but not of hyperparathyroidism or osteoporosis. 2) Many patients with histological osteomalacia and radiological features of osteomalacia, such as fractures or Looser zones, have no symptoms. 3)In dialysis patients, biochemical and radiological abnormalities are not a reliable means of predicting the presence of osteomalacia, but a raised serum alkaline phosphatase is a good indicator of the presence of osteitis fibrosa. For early detection of osteomalacia, bone biopsy in necessary. 4)A number of our dialysis patients develop an unusual form of osteomalacia characterized by absent or minimal histological osteitis fibrosa, a normal serum alkaline phosphatase, and a high incidence of myopathy and fractures.

Adolescent↗

PubMed1993

Radiophosphate imaging and bone densitometry in renal osteodystrophy.

The histologic features of renal osteodystrophy vary from dialysis osteomalacia to osteitis fibrosa cystica. Commensurate with this, the number of osteoblasts and osteoclasts changes with the stage of the disease; the osteoblasts are virtually absent in dialysis osteomalacia and are numerous in osteitis fibrosa. Radiophosphate accretion in bone increases with increasing osteoblastic activity, and the bone mineral status is determined by the net difference in osteoblastic and osteoclastic activity. The application of radionuclide imaging and dual radiographic absorptiometry mineral measurements in patients with renal osteodystrophy, renal transplants, and following parathyroidectomy for secondary hyperparathyroidism is reviewed.

Bone Density↗

PubMed1989

Spontaneous rupture of the quadriceps tendon in patients on maintenance hemodialysis--report of three cases with clinicopathological observations.

Three patients receiving maintenance hemodialysis therapy for end-stage renal failure presented with spontaneous rupture of the quadriceps tendon(s). Biochemical data and the skeletal roentgenograms were compatible with secondary hyperparathyroidism. Histological examination of the excised quadriceps tendon specimens suggested that repeated minor avulsion fractures of the bone cortex at the tendon insertion site had preceded the final total tendon rupture and that osteitis fibrosa was responsible for these minor fractures. Serum alkaline phosphatase level had been increasing continuously for approximately five years prior to the tendon rupture in all three patients, indicating that uncontrolled osteitis fibrosa due to secondary hyperparathyroidism over these years preceded the tendon rupture.

Adult↗

PubMedDate not supplied

[Study of renal osteodystrophy by bone biopsy. Age as an independent factor. Diagnostic value of bone remodeling markers].

The spectrum of bone disease in uremic patients on hemodialysis has changed in the last years. Undecalcified bone biopsy with histomorphometric measurements and tetracycline labelling remains the gold standard for diagnosis of the different forms of renal osteodystrophy. But because of its invasive nature and complicated laboratory processing a number of non-invasive biochemical parameters have been proposed. The aim of our study was to determine the prevalence of the different forms of renal osteodystrophy in our patients in hemodialysis. Moreover we analyse the correlation between several biochemical parameters and the histological findings and evaluate their diagnostic and predictive value. Transiliac bone biopsies were performed in seventy three uremic patients (31 males) on chronic hemodialysis and static and dynamic parameters were measured. Serum levels of intact parathyroid hormone (iPTH), osteocalcin (OC), total alkaline phosphatase (FAT) and bone alkaline phosphatase (FAO) were determined. High-bone remodelling (50 pts, 68.5%) predominates over low-bone remodelling (23 pts, 31.5%). The distribution of the different types of bone disease was: Mild hyperparathyroidism 8 pts, Osteitis fibrosa 37 pts, Mixed lesions 5 pts, Adynamic bone disease 21 pts and Osteomalacia 2 pts. Six of our 73 patients were diabetics and they had adynamic bone disease (4 pts), osteomalacia (1 pt) and osteitis fibrosa (1 pt). Patients older than 50 years presented lower cellular activity (osteoblast surface, ObS/BS) and lower bone formation rate (BFR/BS). iPTH showed different correlation with these parameters of bone formation in patients above and below 50 years old suggesting that older patients need higher levels of PTH to obtain a determined level of bone formation. iPTH, OC, FAT and FAO correlated with the majority of histomorphometric indices of bone formation and resorption, though the best correlations were those with iPTH. The diagnostic and predictive value of these bone markers is better with high-bone remodelling. Serum levels of FAT > 300 U/l, OC > 150 ng/ml, FAO > 40 ng/ml and iPTH > 200 pg/ml showed a positive predictive value of 1 (with a specificity of 1, but sensibility below 0.78 except for iPTH that is 0.95) in the diagnosis of high-bone remodelling. After an analysis with ROC curves the cut-off value to differentiate high from low-bone remodelling was obtained. iPTH level > 200 pg/ml combined with one of the other markers (FAT > 150 U/l, FAO > 30 ng/ml or OC > 100 ng/ml) are predictive of high-bone remodelling, while values below those figures are predictive of low-bone remodelling.

Age Factors↗

PubMed1985

Ectopic calcification. The role of parathyroid hormone.

In 42 uraemic patients radiological skeletal survey, biochemistry and bone histology were compared before and at 6-12 months (42 patients), 12-24 months (26 patients) or 24-48 months (12 patients) after parathyroidectomy. The presence of small vessel or non-visceral soft tissue calcification was not related to the age, sex, duration of end-stage renal failure treatment, total serum calcium, magnesium, phosphate, Ca x P product, alkaline phosphatase, ionised calcium, serum aluminium, iPTH, severity of radiological and histological osteitis fibrosa or parathyroid gland weight. Twenty-three patients (55%) had small vessel and 20 (48%) soft tissue calcification before parathyroidectomy. Despite a marked improvement in subperiosteal erosions (37 healed, 5 improved) and healing of osteitis fibrosa histologically, seven patients developed new and six developed increased peripheral arterial calcification while in 10 patients non-visceral soft tissue calcification disappeared and in two decreased. Successful parathyroidectomy improves non-visceral calcification but not arterial calcification despite reduction in Ca x P product and iPTH.

Adult↗

PubMed1993

Parathyroid gland function in chronic renal failure.

The concept that the PTH-calcium curve is representative of parathyroid function has been discussed. Comparisons of parathyroid function have been made between normal humans and hemodialysis patients and also between hemodialysis patients with different forms of renal osteodystrophy. From these comparisons, it is apparent that the magnitude of HPT is much greater in patients with renal failure than in normal humans, and as represented by the ratio of basal to maximal PTH, the parathyroid gland appears to be stimulated at basal serum calcium levels in hemodialysis patients. Similarly, based on an analysis of the PTH-calcium curve, we were able to determine that several differences in parathyroid function were present in hemodialysis patients with different forms of renal osteodystrophy. As compared to hemodialysis patients with LTAABD and aplastic bone disease, patients with osteitis fibrosa have a greater magnitude of hyperparathyroidism, a greater sensitivity of the parathyroid cell (slope), a higher set point of calcium, and greater PTH stimulation at basal serum calcium (ratio of basal to maximal PTH). Calcitriol treatment of hemodialysis patients with osteitis fibrosa resulted in a significant decrease in PTH throughout the PTH-calcium curve and also reduced the sensitivity (slope) of the PTH-calcium curve. The concept of hysteresis has been discussed as well as the role that the ambient basal serum calcium concentration may have on the determination of the PTH-calcium curve. Finally, the effect that successful renal transplantation has on HPT has been examined. In conclusion, we believe that the PTH-calcium curve provides a reliable assessment of parathyroid function, and as such, has considerable application for the study of parathyroid disorders in the clinical setting.

Calcitriol↗

PubMed1992

[Clinical study of total parathyroidectomy and autotransplantation for secondary hyperparathyroidism].

From April 1983 to September 1991 total parathyroidectomy (PTX) and parathyroid autotransplantation were carried out in 27 patients for secondary hyperparathyroidism. Of these patients, 13 were males and 14 were females. Their average age was 43 years old and their mean duration of dialysis was 126.4 months. As preoperative clinical symptoms, bone pain was observed in 19 cases, joint pain in 18, decrease of height in 7, pruritus in 3, muscle pain in 2, red eyes in 2 and others in 2. As roentgenographic findings, subperiosteal bone resorption and skull-salt and pepper were demonstrated in 26 cases, rugger jersey spine in 15, soft tissue calcification in 11, and pathological fractures in 4. Four parathyroid glands were removed in 23 cases, three glands in 4. Serum calcium level decreased remarkably within 24 hours after parathyroidectomy in all cases. The average total weight of parathyroid glands was 4.48 g. The preoperative diagnostic accuracy of echogram was 94% and that of CT scan was 90%. The clinical improvement after PTX was excellent in 12 cases and good in 11. The roentgenographic improvement of skull and/or finger bone more than one year after PTX was excellent in 11 cases and good in 11. Judging from histopathological findings of the bone, the clinical and roentgenographic improvement was observed better in the osteitis fibrosa group than in mild group. A significant correlation was found between the level of preoperative c-PTH and the weight of resected parathyroid glands. The level of preoperative ALP correlated with intact-PTH and was higher in the osteitis fibrosa group than in the mild group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

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.

Aluminum↗

PubMed1986

Does strict phosphorus control precipitate renal osteomalacia?

Hyperphosphatemia leads to the development of osteitis fibrosa in patients with chronic renal failure. In contrast, crippling osteomalacia may appear in uremic patients who are hypophosphatemic or aluminum intoxicated or who undergo total or subtotal parathyroidectomy. Thus, strict phosphorus control by use of aluminum-containing gels may ameliorate renal osteitis fibrosa, but may potentiate the development of osteomalacia. To evaluate this possibility, we compared the bone histologies of 10 chronic renal hemodialysis patients who consistently maintained predialysis phosphorus levels between 4-5 mg/dl (Strict-P) to those of 46 randomly selected dialysis patients (Random-P). We found that the Strict-P group had lower circulating immunoreactive PTH (P less than 0.02) and alkaline phosphatase (P less than 0.05) levels and, as expected, less evidence of hyperparathyroid bone disease. On the other hand, the Strict-P patients had osteomalacia, as evidenced by moderate osteoid accumulation and reduced capacity of bone to assume a fluorescent tetracycline label. Furthermore, all Strict-P patients had histological evidence of bone aluminum accumulation. We conclude that maintenance of normal serum P levels with aluminum-containing gels in hemodialysis patients prevents severe hyperparathyroid bone disease. Such treatment, however, is also attended by a moderate degree of aluminum-associated osteomalacia.

Adult↗

PubMed1990

[Radiologic changes in the pelvis of patients with chronic renal insufficiency undergoing periodic dialysis].

Bone alterations in the patients undergoing periodic dialysis represent a frequent and invalidating complication and cause the pattern called uremic osteodystrophy. In this study we have examined 173 pelvic X-rays of 73 patients affected with chronic renal insufficiency and undergoing periodic dialysis. The results indicate the presence of all the lesions characterizing uremic osteodystrophy. Arterial calcifications and osteoporosis are the most frequent patterns; with various incidence, osteomalacia, osteitis fibrosa, osteosclerosis and brown tumors are associated. In this group of patients, who were followed for many years, a non-univocal behavior was observed: next to patterns of progressive aggravation, such as vascular calcifications, phases of stabilization/improvement were observed, e.g., in case of brown tumors and osteitis fibrosa.

Adolescent↗

PubMed1977

Quadriceps tendon ruptures in uremia. Treatment with surgery and 1alpha-hydroxycholecalciferol.

Three young patients with chronic renal failure, one on regular hemodialysis, suffered bilateral quadriceps tendon ruptures. All three had uncontrolled, severe osteitis fibrosa. In two, aluminium hydroxide failed to control secondary hyperparathyroidism, while 1alpha-hydroxycholecalciferol (1alphaOHD3) given after the injury resulted in rapid resolution of the hyperparathyroidism. Prevention of tendon ruptures in uremia depends on effective control of secondary hyperparathyroidism. Treatment should involve prompt surgical repair and reversal of the osteitis fibrosa with an effective vitamin D metabolite such as 1alphaOHD3.

Adolescent↗