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H H Malluche

Publications and source records attributed to H H Malluche.

At least 19 recordsLinked to original sources
PubMed1992

Dose-dependent effects of aluminum on osteocalcin synthesis in osteoblast-like ROS 17/2 cells in culture.

This in vitro study evaluates the effect of aluminum (Al3+) on osteocalcin, a small protein that is produced by the osteoblast. After stimulation with various doses of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; 10(-11) to 10(-9) M], osteocalcin was consistently lower in the culture medium of ROS 17/2 osteoblastic cells conditioned with 5 microM Al(3+)-saturated transferrin (AlTR) than in apotransferrin (ApoTR)-treated controls. In a second experiment, cultures were conditioned with various doses of AlTR or ApoTR (1.6-8.0 microM) and stimulated with 10(-9) M 1,25(OH)2D3. High doses of AlTR (4.8-8.0 microM) resulted in lower medium and unchanged intracellular content of osteocalcin than treatment with equal amounts of ApoTR. However, in the same experiment, lower doses of AlTR or ApoTR (1.6 and 3.2 microM) yielded different results, i.e., increased medium and intracellular contents of osteocalcin in the Al(3+)-treated cells. Expression of osteocalcin mRNA was not altered in cultures conditioned with low (1.6 microM) or high (8.0 microM) concentrations of AlTR or ApoTR. Similarly, no effect of Al3+ was observed on total protein content, the rate of total protein synthesis, and the degradation of secreted osteocalcin in cultures conditioned with various doses of AlTR or ApoTR. These findings suggest that AlTR affects osteocalcin synthesis in a specific manner, without concomitant effects on the rate of total protein synthesis or on the rate of degradation of osteocalcin. This effect is dose dependent, i.e., low doses of AlTR stimulate and high doses suppress osteocalcin synthesis and/or secretion, and it appears to be posttranscriptional, since the expression of osteocalcin mRNA is not affected.

Aluminum↗
PubMed1992

The possible use of bisphosphonates in the treatment of renal osteodystrophy.

Bisphosphonates appear to provide an attractive, novel approach in the management of patients with uremic bone disease. Only limited studies are available. Based on the understanding of the pathogenesis of renal bone disease, three major indications for the use of bisphosphonates in patients with uremic bone disease emerge: 1. Hypercalcemia related to increased release of calcium from bone. 2. Excessive elevation of bone turnover related to increased parathyroid hormone effects. 3. Extraosseous calcifications due to high calcium phosphorus product. Moreover, further studies may reveal how the combination between bisphosphonates and 1,25 vitamin D therapy might affect uremic bone. Details on doses, mode of administration (continuously vs. intermittently) and optimal duration of therapy should be tested in an animal model of uremic bone disease.

Chronic Kidney Disease-Mineral and Bone Disorder↗
PubMed1992

Risk of adynamic bone disease in dialyzed patients.

Renal osteodystrophy presents with a spectrum of histologic abnormalities. A new entity characterized by a marked decrease in bone turnover without osteoid accumulation, that is, adynamic bone disease, has recently emerged. This new form was thought to be primarily related to aluminum accumulation. Since aluminum-containing phosphate binders have been widely replaced by calcium salts, adynamic bone disease would be expected to disappear over time. However, not only is adynamic bone disease observed in the absence of aluminum intoxication, its incidence does not seem to have decreased. We conducted a retrospective study in 1,803 patients on chronic maintenance dialysis who were biopsied during the last 10 years and assessed the incidence of adynamic bone disease over time in an effort to elucidate the factors associated with its occurrence. Adynamic bone disease was first seen in 1984 in the laboratory. Its incidence increased gradually over the years and, in 1991, still affected approximately 20% of the patients. The primary factors associated with the occurrence of adynamic bone disease include: (a) aluminum accumulation which is currently found in 60% of the patients on chronic maintenance dialysis undergoing biopsies, (b) increasing age of the patients on dialysis, (c) diabetes, and, possibly, (d) chronic ambulatory peritoneal dialysis. The clinical relevance of adynamic bone disease deserves further study. At present, this entity is associated with a tendency towards hypercalcemia, aging of bone due to stunted bone remodeling, a condition which might be associated with impaired repair of physiologic microdamages, and accumulation of microfractures leading to mechanical incompetence and ultimately to higher risk of fractures.

Adolescent↗
PubMed1991

Uremic bone disease: current knowledge, controversial issues, and new horizons.

Abnormalities in mineral and bone metabolism occur early in the course of renal failure and uremic bone disease is a major contributing factor to the morbidity of patients with end-stage renal failure. In addition, new therapeutic approaches have generated new outlooks, problems and controversies. This article reviews our current accepted knowledge, the present numerous controversies, unresolved questions, new issues and new horizons.

Aluminum↗
PubMed1990

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.

Animals↗
PubMed1990

Regulation of 25-hydroxyvitamin D3 metabolism in cultures of osteoblastic cells.

This study was designed to investigate the mechanisms involved in the regulation of the conversion of 25-hydroxyvitamin D3 (25-OHD3) to 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] in primary cultures of osteoblastlike cells from neonatal mouse calvariae. These cells, when incubated with tritiated 25-OHD3 ([3H]25-OHD3), spontaneously synthesized [3H]24,25-(OH)2D3 20-50 times more efficiently than [3H]1,25-(OH)2D3 at a rate of conversion that was substrate dependent and linear from 1 to 36 h. Gas chromatography-mass spectrometry verified the identity of the dihydroxylated metabolites. The calcium ionophore A23187 (5 microM) consistently stimulated the synthesis of 1,25-(OH)2D3 while suppressing the production of 24,25-(OH)2D3. This effect was sustained for 36 h and was dose dependent for concentrations from 0.05 to 10 microM. Furthermore, A23187 stimulated cAMP production and indomethacin (50 ng/ml) blocked the A23187-induced production of cAMP and 1,25-(OH)2D3 but had no effect on the suppression of 24,25-(OH)2D3 by A23187. This led to other experiments to find out whether the stimulative effect of A23187 on 1,25-(OH)2D3 synthesis is mediated by prostaglandins or cAMP, or both. PGE2 (10(-8)-10(-6) M) increased the production of 1,25-(OH)2D3 and of 24,25-(OH)2D3. Forskolin (0.01-10 microM) and dibutyryl cAMP (0.1-10 mM) increased the production of both metabolites but to a lesser degree than PGE2. These data suggest that osteoblastlike cells are stimulated by A23187 to increase the synthesis of 1,25-(OH)2D3 through mechanisms involving prostaglandins and cAMP. The synthesis of 24,25-(OH)2D3 is suppressed by A23187 through different mechanisms.

24,25-Dihydroxyvitamin D 3↗
PubMed1990

Role of calcitriol in the management of osteoporosis.

Ovariohysterectomized Beagle dogs provide a useful model for the study of bone loss following cessation of ovarian function. Data obtained in our laboratory suggest that the sequence of events occurring after cessation of such function proceeds in two phases. The first, or "initiation," phase begins within 1 month after ovariohysterectomy (OHX). Although the number of osteoclasts is unchanged, there is an increase in trabecular separation, accompanied by a dramatic decrease in cancellous bone volume, which suggests an apparent dramatic hyperresorption. This early phase is followed by a "maintenance" phase, which commences in the second month and is related to an osteoblastic insufficiency. In another experiment, administration of 1,25(OH)2D3 corrected bone loss occurring after OHX in Beagle dogs. However, a positive balance between increased bone cell activity and decreased bone cell number was not maintained. This calls for new strategies to separate the positive effect of 1,25(OH)2D3 on bone cell activity from the negative effect on bone cell number.

Animals↗
PubMed1990

Five-year postoperative results of cemented femoral arthroplasty in patients with systemic bone disease.

To determine whether bone cellular abnormality affects the results of cemented femoral arthroplasty, 21 patients had biopsies of the iliac crest and femoral cortex at the time of surgery. Roentgenographic and histomorphometric studies were used to characterize fibrous membrane formation, cancellous bone, calcar resorption, and bone turnover. Patients with high bone turnover and decreased femoral thickness and density before surgery were at risk of developing calcar resorption and cancellous diaphyses, conditions that weaken proximal stem support and lead to early failure. These findings suggest that noncemented stems may be indicated in this group. Another group, osteoporotic patients, suffered from osteoblastic insufficiency, which may be the indication for the use of cemented stems rather than noncemented stems, which require bony ingrowth.

Aged↗
PubMed1989

1,25(OH)2D3 administration in moderate renal failure: a prospective double-blind trial.

This study represents the first randomized prospective, double-blind, placebo-controlled trial of the efficacy of 1,25(OH)2D3 on bone histology and serum biochemistry in patients with mild to moderate renal failure. Sixteen patients with chronic renal impairment (creatinine clearance 20 to 59 ml per min) received either 1,25(OH)2D3, at a dose of 0.25 to 0.5 microgram daily (eight patients), or placebo. Transiliac crest bone biopsies were performed before entrance into the study and after 12 months of experimental observation. None of the patients were symptomatic or had radiological evidence of bone disease. Of the thirteen patients who completed the study, initial serum 1,25(OH)2D levels were low in seven patients and parathyroid hormone levels were elevated in seven patients. Bone histology was abnormal in all patients. 1,25(OH)2D3 treatment was associated with a significant fall in serum phosphorus and alkaline phosphatase concentrations as well as with histological evidence of an amelioration of hyperparathyroid changes. In contrast to previous reports, no deterioration of renal function attributable to the treatment occurred, perhaps because a modest dose of 1,25(OH)2D3 was employed combined with meticulous monitoring. Further investigation is required to determine whether alternative therapeutic strategies (smaller doses or intermittent therapy) may avoid the potential for suppressing bone turnover to abnormally low levels in the long term.

Adult↗
PubMed1989

Early therapy of renal bone disease with calcitriol: a prospective double-blind study.

The value of calcitriol administration in the management and prevention of renal bone disease was studied in a prospective double-blind manner in 16 patients with chronic renal impairment (creatinine clearance 20 to 59 ml per min). They were given either calcitriol at a dose of 0.25 to 0.5 micrograms daily (eight patients), or placebo. Transiliac crest bone biopsies were performed before entrance into the study and after 12 months of experimental observation. None of the patients were symptomatic or had biochemical or radiological evidence of bone disease. Of the thirteen patients who completed the study, initial serum 1,25(OH)2D levels were low in seven patients and parathyroid hormone levels were elevated in seven patients. Bone histology was abnormal in all patients. Calcitriol treatment was associated with a significant fall in serum phosphorus concentrations and alkaline phosphatase levels as well as with histological evidence of an amelioration of hyperparathyroid changes. In contrast to previous reports, no deterioration of renal function attributable to the treatment occurred, perhaps because a modest dose of calcitriol was employed combined with meticulous monitoring. Further investigation is required to determine whether alternative therapeutic strategies (smaller doses or intermittent therapy) may avoid the potential for suppressing bone turnover to abnormally low levels in the long term.

Bone Diseases↗
PubMed1988

Effect of 1,25-vitamin D and parathyroidectomy on the uptake of aluminum in bone of rats with renal insufficiency.

Excessive aluminum accumulation in bone is associated with abnormalities in bone formation and mineralization in man and animals. The factors that influence deposition of aluminum in bone are not well understood. In this study the influence of 1,25-vitamin D on bone aluminum accumulation was evaluated in aluminum-loaded parathyroidectomized and nonparathyroidectomized rats with renal insufficiency. All groups of aluminum-loaded rats receiving 1,25-vitamin D had less bone aluminum accumulation. This effect was not influenced by the presence of absence of parathyroid hormone. All rats administered 1,25-vitamin D had elevated serum calcium and depressed serum phosphorus levels and lower body weight compared to controls. The results ascribe a potential role for 1,25-vitamin D in the prevention of aluminum accumulation.

Aluminum↗
PubMed1988

Aluminum-related bone disease.

Only rather recently has the biologic and pathogenetic relevance of aluminum, this most common metal come under serious scientific scrutiny. Various laboratory findings of accumulations of aluminum in the brain, kidney, liver, parathyroid glands, skeletal muscle, heart, lungs, pancreas and spleen as well as stainable aluminum in bone have spurred widespread interest in aluminum absorption and toxicity and in the mechanisms involved in the metabolism of aluminum. Since the kidney is the major excretory organ for aluminum, this report focuses on the abnormalities occurring with aluminum accumulation in the bone of patients with renal failure to determine the metabolic interrelationships of aluminum, parathyroid hormone, vitamin D, iron, and calcium. This editorial presents an overview of the most recent investigations of aluminum accumulation in humans, experimental animal models, and at the cellular level, presents the metabolic relationships known to exist as well as those strongly suggested in documented studies, and identifies those aspects of aluminum-related bone disease awaiting study in this increasingly important field of inquiry. The study outlines the metabolism of aluminum, the pathogenesis, prevalence, morbidity and mortality of aluminum-related bone disease, the histopathology of bone with aluminum accumulation, the recognized difficulties inherent in the diagnosis of aluminum-related bone disease, and the current understanding as relates to prevention and therapy.

Aluminum↗