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Biomedical subjects

R M Friedler

Publications and source records attributed to R M Friedler.

At least 19 recordsLinked to original sources
PubMed2001

Improved assessment of bone turnover by the PTH-(1-84)/large C-PTH fragments ratio in ESRD patients.

BACKGROUND: The "intact" parathyroid hormone (PTH) assay recognizes PTH-(1-84) as well as amino terminally truncated PTH fragments, that is, large carboxyterminal PTH fragments (C-PTH fragments). The present study investigated whether the use of the plasma PTH-(1-84)/C-PTH fragment ratio enhances the noninvasive assessment of bone turnover in patients on dialysis. METHODS: Bone biopsies and blood samples for determinations of routine indices of bone turnover and PTH peptides were obtained in 51 adult patients on dialysis not treated with drugs affecting bone such as vitamin D or corticosteroids. Blood levels of large C-PTH fragments were calculated by subtracting PTH-(1-84) from "intact" PTH. Patients were classified according to their levels of bone turnover based on histomorphometrically obtained results of activation frequency. Prediction of bone turnover by the various blood indices was done by using proper statistical methods. In addition, hypercalcemia was induced by calcium gluconate infusion in a subset of patients, and levels of PTH-(1-84), "intact" PTH, and PTH-(1-84)/C-PTH fragment ratio were determined. RESULTS: The PTH-(1-84)/C-PTH fragment ratio was the best predictor of bone turnover. A ratio> 1 predicted high or normal bone turnover (sensitivity 100%), whereas a ratio <1 indicated a high probability (sensitivity 87.5%) of low bone turnover. Calcium infusion resulted in decrease in PTH-(1-84)/C-PTH fragment ratio. CONCLUSIONS: The PTH-(1-84)/C-PTH fragment ratio predicts bone turnover with acceptable precision for biological measurements. Moreover, a change in serum calcium levels is one of the regulators of the relative amount of circulating PTH-(1-84) and its large C-PTH fragments.

Adult↗
PubMed1999

22-oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure.

BACKGROUND: Calcitriol therapy suppresses serum levels of parathyroid hormone (PTH) in patients with renal failure but has several drawbacks, including hypercalcemia and/or marked suppression of bone turnover, which may lead to adynamic bone disease. A new vitamin D analogue, 22-oxacalcitriol (OCT), has been shown to have promising characteristics. This study was undertaken to determine the effects of OCT on serum PTH levels and bone turnover in states of normal or impaired renal function. METHODS: Sixty dogs were either nephrectomized (Nx, N = 38) or sham-operated (Sham, N = 22). The animals received supplemental phosphate to enhance PTH secretion. Fourteen weeks after the start of phosphate supplementation, half of the Nx and Sham dogs received doses of OCT (three times per week); the other half were given vehicle for 60 weeks. Thereafter, the treatment modalities for a subset of animals were crossed over for an additional eight months. Biochemical and hormonal indices of calcium and bone metabolism were measured throughout the study, and bone biopsies were done at baseline, 60 weeks after OCT or vehicle treatment, and at the end of the crossover period. RESULTS: In Nx dogs, OCT significantly decreased serum PTH levels soon after the induction of renal insufficiency. In long-standing secondary hyperparathyroidism, OCT (0.03 microg/kg) stabilized serum PTH levels during the first months. Serum PTH levels rose thereafter, but the rise was less pronounced compared with baseline than the rise seen in Nx control. These effects were accompanied by episodes of hypercalcemia and hyperphosphatemia. In animals with normal renal function, OCT induced a transient decrease in serum PTH levels at a dose of 0.1 microg/kg, which was not sustained with lowering of the doses. In Nx dogs, OCT reversed abnormal bone formation, such as woven osteoid and fibrosis, but did not significantly alter the level of bone turnover. In addition, OCT improved mineralization lag time, (that is, the rate at which osteoid mineralizes) in both Nx and Sham dogs. CONCLUSIONS: These results indicate that even though OCT does not completely prevent the occurrence of hypercalcemia in experimental dogs with renal insufficiency, it may be of use in the management of secondary hyperparathyroidism because it does not induce low bone turnover and, therefore, does not increase the risk of adynamic bone disease.

Animals↗
PubMed1993

A new bisphosphonate, BM 21.0955, prevents bone loss associated with cessation of ovarian function in experimental dogs.

We previously found that bone loss occurs as soon as 1 month after ovariohysterectomy (OHX) in beagle dogs. Indirect evidence pointed to an early dramatic increase in bone resorption. To verify this hypothesis and evaluate the effects of a newly developed bisphosphonate, BM 21.0955 (Boehringer Mannheim), 36 beagle dogs were subjected to OHX and 12 dogs were sham operated (Sham). OHX dogs were divided into six groups (n = 6 each) and received subcutaneous injections of vehicle or BM 21.0955 at various doses (0.1, 0.3, 1, 10, and 100 micrograms/kg/day) for 1 month. Sham dogs were given vehicle (n = 6) or BM 21.0955 (1 microgram/kg/day, n = 6). Iliac crest biopsies and blood drawings were done at baseline and at month 1. OHX dogs given vehicle exhibited a decrease in cancellous bone volume associated with an increase in erosion depth and a decrease in serum levels of 1,25-dihydroxyvitamin D. BM 21.0955 prevented the bone loss at a dose > or = 1 microgram/kg and the increase in erosion depth and the decrease in serum levels of 1,25-(OH)2D at a dose > or = 0.3 microgram/kg. No osteomalacia was observed at any dose of BM 21.0955. Bone turnover was reduced only when BM 21.0955 was administered at doses of 10 or 100 micrograms/kg. There were no changes in body weight or serum levels of calcium, phosphorus, creatinine, parathyroid hormone, or osteocalcin in all groups. The increase in erosion depth in OHX dogs given vehicle proves that the early rapid bone loss after cessation of ovarian function is related to an increase in osteoclastic activity. The antiosteoclastic activity of BM 21.0955 at a dose > or = 1 microgram/kg prevents this increase and preserves bone volume. The absence of any signs of osteomalacia at any dose confers a relatively wide therapeutic margin to BM 21.0955. BM 21.0955 at a dose > or = 10 micrograms/kg also acts as an inhibitor of bone turnover. This is not observed at a dose of 1 microgram/kg, at least after 1 month of administration.

Animals↗
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↗
PubMed1988

1,25-dihydroxyvitamin D3 corrects bone loss but suppresses bone remodeling in ovariohysterectomized beagle dogs.

The decrease in intestinal calcium absorption and lower blood levels of 1,25-dihydroxyvitamin D [1,25-(OH)2D3] have been implicated in the pathogenesis of postmenopausal osteoporosis. This study evaluates the effects on bone of 1,25-(OH)2D3 therapy using the ovariohysterectomized dog model. The cessation of ovarian function was ascertained by an increase in serum LH levels 4 weeks after ovariohysterectomy, and significant bone loss was revealed four months after ovariohysterectomy. The bone loss was associated with an increase in the number of bone-forming cells and a decrease in the activity of these cells. The administration of 1,25-(OH)2D3 increased the activity of the bone cells and resulted in a reversal of all abnormalities in structural parameters of bone, including cancellous bone mass, trabecular wall thickness, trabecular plate separation, trabecular plate density, and trabecular plate thickness (which increased above normal). However, 1,25-(OH)2D3 therapy was also associated with a significant decrease in the number of bone-forming cells, resulting in lower bone formation at the tissue level. The results of this study indicate that 1,25-(OH)2D3 therapy can reverse the bone loss and osteoblastic insufficiency responsible for the maintenance of negative bone balance after the cessation of ovarian function. However, this therapy has a suppressive effect on bone cell number and bone turnover. This undesired side-effect of 1,25-(OH)2D3 therapy renders a chronic therapeutic regimen inefficient for the long term management of patients with osteoporosis. Intermittent 1,25-(OH)2D3 therapy or a sequential therapy using 1,25-(OH)2D3 along with substances known to increase the number of bone-forming cells is strongly suggested by these results.

Animals↗
PubMed1987

Calcitriol, parathyroid hormone, and accumulation of aluminum in bone in dogs with renal failure.

Accumulation of aluminum in bone is a frequent finding in patients requiring chronic dialysis and is associated with considerable morbidity and/or mortality. Until now, evidence seemed to point to relatively low circulating levels of parathyroid hormone as a contributing factor, but because levels of parathyroid hormone and calcitriol are interrelated, calcitriol might be also involved. In this study we employed an animal model to evaluate the single and combined effects of parathyroid hormone and calcitriol on bone aluminum accumulation. The results show significantly less aluminum accumulation in calcitriol-replete dogs independent of the presence or absence of parathyroid hormone. These results indicate that low levels of calcitriol may play a role in the development of aluminum related bone disease. Further studies are needed to demonstrate whether administration of calcitriol in patients with renal insufficiency will prevent development of aluminum-related bone disease.

Aluminum↗
PubMed1986

1,25-Dihydroxyvitamin D maintains bone cell activity, and parathyroid hormone modulates bone cell number in dogs.

The singular and combined effects of 1,25-dihydroxyvitamin D [1,25-(OH)2D] and PTH on bone were evaluated in a long term in vivo study in dogs. Dogs were rendered deficient in 1,25-(OH)2D and PTH by five sixths nephrectomy and parathyroidectomy. A control group was sham operated. Various combinations in status of 1,25-(OH)2D and PTH were produced by daily sc injections of 1,25-(OH)2D (1.25) and/or continuous infusion of 1-34 bovine PTH. These were 1.25+/PTH+, 1.25-/PTH-, 1.25+/PTH-, 1.25-/PTH+. Serum calcium levels were kept in the normal range by the administration of one or two of the hormones or by oral supplementation of calcium lactate. Histomorphometric evaluation of static and dynamic parameters of bone after 8 months of experimental observation revealed that deficiency in 1,25-(OH)2D and PTH resulted in decreased number and activity of bone-forming and resorbing cells. Administration of 1,25-(OH)2D increased the activity but not the number of bone cells. In contrast, administration of PTH increased the number but not the activity of bone cells. Tissue level activity was decreased when one or both hormones were deficient, and normal tissue level activity was found only when both hormones were given. These data are relevant for understanding and management of diseases with perturbations in vitamin D and/or PTH.

Animals↗
PubMed1985

Nephrogenous cyclic AMP during extracellular volume expansion: relationship to early and late aortic constriction.

Prior data showed that both volume expansion (ECVE) and renal vasodilatation are associated with natriuresis and increased nephrogenous cAMP (NcAMP). Studies were done to examine the effect of ECVE on sodium excretion and NcAMP during early or late reduction in renal perfusion pressure (RPP) in an effort to define the role of renal vasodilatation on NcAMP during ECVE. In 8 thyroparathyroidectomized (TPTX) dogs, RPP to the left kidney was reduced (130 +/- 1.7 to 69 +/- 4 mm Hg), ECVE was then produced and finally RPP was allowed to rise to 126 +/- 2.2 mm Hg (group I). In 8 TPTX, ECVE was produced and then followed by a reduction in RPP (121 +/- 5 to 69 +/- 5 mm Hg; group II). cAMP was measured in aorta, renal veins and urine. In group I, renal plasma flow (RPF), fractional excretion of Na filtered (FeNa), urinary NcAMP (UNcAMP) and renal vein NcAMP (RVNcAMP) did not change in the constricted kidney while these parameters increased in the other kidney. After release of the constriction RPF (122 +/- 24 to 157 +/- 26 ml/min), FeNa (0.5 +/- 0.1 to 5 +/- 1.2%), UNcAMP (204 +/- 121 to 785 +/- 198 pmol/min, p less than 0.05) and RVNcAMP (277 +/- 213 to 1,565 +/- 403 pmol/min, p less than 0.02) rose significantly. In group II, FeNa, UNcAMP and RVNcAMP increased during ECVE and remained significantly elevated during the reduction in RPP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension.

To examine the mechanisms underlying the sensitivity to sodium intake in a subset of patients with essential hypertension, we studied the effects of different sodium intake (10, 100, 200 mEq/day) on blood pressure, the function of the renin-angiotensin-aldosterone system, and on blood levels of catecholamines in 20 patients with essential hypertension and 10 normal subjects. Mean blood pressure (MBP) was not different in hypertensive and normal subjects during low sodium diet. But, with high sodium intake, MBP increased by at least 10% in 12 patients (salt-sensitive), whereas in the remaining 8 patients (salt-resistant) and in normal subjects, MBP did not change significantly. This phenomenon cannot be attributed to differences in sodium retention because the percent change in body weight ad the urinary sodium excretion in the salt-sensitive patients was not different than it was in salt-resistant patients or in normal subjects. The observed difference in blood pressure response to high sodium intake in salt-sensitive patients is also not dependent on an impaired suppressibility of the renin-angiotensin-aldosterone system because there were no significant differences in the basal levels of PRA and aldosterone between the groups, and because the orthostatic increments in PRA were significantly lower in salt sensitive than they were in the salt-resistant patients and in normal subjects. Plasma norepinephrine (NE) levels were not significantly different between normal subjects or hypertensive patients while on low sodium intake. But during high sodium intake, they decreased significantly (P less than 0.05) in normal subjects (from 22 +/- 3.4 to 12 +/- 2.3 ng/dl) and in salt-resistant patients (from 17 +/- 4.5 to 13 +/- 2.4 ng/dl) but not in salt-sensitive patients (from 20 +/- 1.9 to 22 +/- 3.2 ng/dl). Furthermore, the majority of salt-sensitive patients displayed inappropriately high plasma NE in relation to their urine excretion of sodium during high sodium intake. Finally, the increments in plasma NE after 5 min of standing were significantly greater in salt-sensitive patients than they were in salt-resistant patients and normal subjects during both low or high sodium intake. These data indicate that a subset of patients with essential hypertension may have impaired suppressibility of plasma NE during high sodium intake, which suggests hyperactivity of the sympathetic nervous system in these patients. These aberrations may be responsible for the increase in MBP in the salt-sensitive patients during high sodium intake.

Adult↗
PubMed1977

Role of cyclic AMP in the natriuresis of extracellular fluid volume expansion in the dog.

1. The effect of extracellular volume expansion (ECVE) on renal production of cyclic AMP was evaluated in 19 thyroparathyroidectomized dogs. ECVE was produced by the infusion of Ringer bicarbonate solution at a rate of 2 ml min-1 kg-1 body weight; cyclic AMP was measured in plasma obtained from the aorta and renal vein and in the urine. 2. During the natriuresis of ECVE urinary excretion of cyclic AMP, the clearance of cyclic AMP, net nephrogenous cyclic AMP added both to urine and to the renal vein and hence total nephrogenous cyclic AMP increased significantly. 3. This rise in net production of cyclic AMP and a significant natriuresis by the kidney persisted for 60--90 min after discontinuation of active ECVE and return of renal plasma flow to normal. 4. The results support the notion that an increase in the production of cyclic AMP by the kidney may play a role in the natriuresis of ECVE.

Adenylyl Cyclases↗