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Biomedical subjects

H Fleisch

Publications and source records attributed to H Fleisch.

At least 19 recordsLinked to original sources
PubMed2003

Bisphosphonates in osteoporosis.

Bisphosphonates are compounds characterized by a P-C-P structure. They act essentially on bone, inhibiting bone resorption. Through this mechanism they decrease bone loss, increase bone mineral density, and decrease bone turnover. They are therefore administered in diseases with elevated bone destruction, such as Paget's disease, metastatic bone disease, and osteoporosis. In the latter they diminish both vertebral and nonvertebral fractures. The adverse events are few, mostly gastrointestinal, and can be avoided to a large extent by correct administration. Since there are no other compounds available which have a similar profile, they represent today the drugs of choice in the treatment and the secondary prevention of osteoporosis.

Adult↗
PubMed1998

Current use of bisphosphonates in oncology. International Bone and Cancer Study Group.

PURPOSE: The purpose of this article is to review the recent data on bisphosphonate use in oncology and to provide some guidelines on the indications for their use in cancer patients. DESIGN: The group consensus reached by experts on the rationale for the use of bisphosphonates in cancer patients and their current indications for the treatment of tumor-induced hypercalcemia and metastatic bone pain in advanced disease and for the prevention of the complications of multiple myeloma and of metastatic bone disease are reviewed. RESULTS: Bisphosphonates are potent inhibitors of tumor-induced osteoclast-mediated bone resorption. They now constitute the standard treatment for cancer hypercalcemia, for which we recommend a dose of 1,500 mg of clodronate or 90 mg of pamidronate; the latter compound is more potent and has a longer lasting effect. Intravenous bisphosphonates exert clinically relevant analgesic effects in patients with metastatic bone pain. Regular pamidronate infusions can also achieve a partial objective response by conventional International Union Against Cancer criteria and enhance the objective response rate to chemotherapy. In breast cancer, the prolonged administration of oral clodronate 1,600 mg daily reduces the frequency of morbid skeletal events by more than one fourth, whereas monthly pamidronate infusions of 90 mg for only 1 year in addition to chemotherapy reduce by more than one third the frequency of all skeletal-related events. The use of bisphosphonates to prevent bone metastases remains experimental. Last, bisphosphonates in addition to chemotherapy are superior to chemotherapy alone in patients with stages II and III multiple myeloma and can reduce the skeletal morbidity rate by approximately one half. CONCLUSION: Bisphosphonate use is a major therapeutic advance in the management of the skeletal morbidity caused by metastatic breast cancer or multiple myeloma, although many questions remain unanswered, notably regarding the optimal selection of patients and the duration of treatment.

Analgesics, Non-Narcotic↗
PubMed1997

Ipriflavone inhibits bone resorption in intact and ovariectomized rats.

The aim of this study was to investigate the possible inhibitory effect of ipriflavone on bone resorption in rats. For this purpose, 10-week-old, intact and ovariectomized (OVX) rats, prelabeled from birth with [3H]-tetracycline, were used. Bone resorption was monitored by measuring the urinary excretion of [3H]. The animals were fed a purified diet devoid of naturally occurring flavonoids. In the intact rats, the daily meal was given either as a single portion or divided into four portions, a procedure known to lead by itself to a decrease in bone resorption. Ipriflavone, given 7 days after OVX at the dose of 400 mg/kg B.W. daily mixed with the food, led within 2-3 days to a significant decrease in bone resorption equivalent to that of 27.2 micrograms/kg s.c. of 17 beta-estradiol. The inhibition was sustained for the length of the experiment, up to 21 days. Ipriflavone given 7 days before OVX prevented the increase in bone resorption induced by castration, the effect being dose-dependent between 50 and 400 mg/kg B.W. In contrast to 17 beta-estradiol, a 5-week treatment with ipriflavone failed to prevent the OVX-induced uterine atrophy. Significant inhibition of bone resorption was also seen in intact animals, provided they rapidly ingested the daily meal. Actually, the decrease in bone resorption induced by portioning the daily food masked the inhibitory effect of ipriflavone in intact animals. In conclusion, ipriflavone can decrease bone resorption in both intact and OVX animals given a purified diet as a single daily meal. In the OVX model, ipriflavone mimics the osteoprotective effect of estrogen. However, the lack of a uterotropic effect suggests that the compound can discriminate between bone and reproductive tissues.

Administration, Oral↗
PubMed1997

Bisphosphonates: mechanisms of action and clinical use in osteoporosis--an update.

Bisphosphonates are a new class of compounds with the ability to decrease bone resorption. Their mode of action appears to be complex, involving both a direct effect on the osteoclasts and an indirect one through osteoblasts. They are currently the drugs of choice in humans for Paget's disease and tumor bone disease, and are most useful in various types of osteoporosis. In view of their low toxicity, they are a most valuable addition to our therapeutic possibilities in the treatment of bone diseases.

Bone Resorption↗
PubMed1997

Mechanisms of action of the bisphosphonates.

Geminal bisphosphonates, usually called bisphosphonates, are synthetic compounds characterized by a P-C-P bond. Many such bisphosphonates have been synthesized, each of them having its own physicochemical and biologic characteristics. This implies that it is not possible to extrapolate from the results of one compound to others with respect to their actions. Bisphosphonates can exert physicochemical effects very similar to those of polyphosphates, binding to the surface of calcium phosphate crystals and inhibiting their formation and aggregation as well as their dissolution. Many of the bisphosphonates are very powerful inhibitors of bone resorption. This is seen both in normal animals and in animals where bone resorption is simulated by various means. Thus, they are active in various models of human diseases, such as hyperparathyroidism, tumoral bone disease and osteoporosis. They not only prevent bone loss, but actively increase bone mass and improve the biomechanical properties of the skeleton. The activity varies greatly from compound to compound, the newest bisphosphonates being 5,000 to 10,000 times more active than etidronate, the first bisphosphonate described. The mechanism of action appears to be complex. It involves: a) a direct effect on the osteoclast activity. b) A direct and indirect effect on the osteoclast recruitment. The latter is mediated by cells of the osteoblastic lineage and involves their production of an inhibitor of osteoclastic recruitment. c) A shortening of osteoclast survival by apoptosis. Large amounts of bisphosphonates can also inhibit mineralization through a physicochemical inhibition of crystal growth. Bisphosphonates are used therapeutically in humans to decrease bone resorption, among others in Paget's disease, tumor bone disease, and recently osteoporosis. Etidronate is also sometimes used to prevent ectopic calcification.

Animals↗
PubMed1996

Synthesis of membrane- and matrix-bound colony-stimulating factor-1 by cultured osteoblasts.

Colony-stimulating factor-1 (CSF-1) is synthesized as a secreted or membrane-bound molecule. We investigated whether osteoblastic cells produce these forms of CSF-1. Glutaraldehyde-fixed cell layers supported proliferation of the macrophage cell line BAC1.2F5, suggesting the presence of membrane- or/and matrix-associated CSF-1. Furthermore, CSF-1 activity could be either extracted from the matrix or released from the cell membrane. A neutralizing antiserum against CSF-1 inhibited these activities. After labeling the cellular proteins with [35S] met/cys or [35S] SO4(2-), CSF-1 was immunoprecipitated and analyzed by SDS-PAGE. Under nonreducing conditions, bands with MW more than 200, 200, 100, and 50 kd were detected. These bands shifted to lower MW under reducing conditions. Treatment with chondroitin lyase ABC decreased the MW of the 200 kd monomer, proving the proteoglycan structure. Much smaller quantities of CSF-1 were found in the matrix extract than in the conditioned medium. Transforming growth factor beta (TGF-beta) increased both the synthesis of CSF-1 and its accumulation in the matrix. CSF-1 released with trypsin from the membrane fraction yielded on SDS-PAGE a band with MW of 60 and 30 kd under nonreducing and reducing conditions, respectively. Transcripts encoding both the secreted and the membrane-associated forms of the cytokine were detected in osteoblasts by reverse transcription polymerase chain reaction. These data indicate that osteoblastic cells produce the secreted forms, either remaining in the culture supernatant, or being associated to the matrix, and the membrane associated form of CSF-1.

Animals↗
PubMed1996

The bisphosphonate ibandronate, given daily as well as discontinuously, decreases bone resorption and increases calcium retention as assessed by 45Ca kinetics in the intact rat.

The new bisphosphonate ibandronate was given at various doses and regimens to normal growing rats, and its effect on calcium metabolism investigated by means of 45Ca kinetics. The bisphosphonate began to inhibit bone resorption at a dose of 0.1 microgram P/kg, given daily. At higher doses intestinal calcium absorption, calciuria and calcium balance were also increased, calcemia being decreased. There was no difference in effect when the same amount of compound was given either daily for 10 days or all at once. Furthermore, the effect of a high dose of 100 micrograms P/kg was present 1 month after a single administration, whereas a dose 10 times lower was no longer effective. These results suggest that ibandronate may be effective in humans for decreasing bone resorption and increasing calcium balance in osteoporosis, when given either daily or discontinuously.

Animals↗
PubMed1996

Effect of bisphosphonates on the increase in bone resorption induced by a low calcium diet.

This study investigates whether bisphosphonate-treated rats are still able to adapt to low calcium supply through an increase in bone resorption assessed by measuring the urinary excretion of [3H]-tetracycline from chronically prelabeled rats. First it was shown that in this model, parathyroid hormone was responsible for the increase in bone resorption on the low calcium diet. In the second part, animals were treated with the three bisphosphonates-clodronate, alendronate, and ibandronate-given in two doses. Animals receiving a dose that already strongly inhibits bone resorption were still able to respond to a low calcium diet by increasing bone resorption, showing the potency of the latter as a stimulator of bone resorption. Higher doses were, however, able to blunt this response. As soon as the treatment was discontinued, this increase in bone resorption resumed with clodronate but not with alendronate or ibandronate.

Alendronate↗
PubMed1996

Characterization and cloning of the E11 antigen, a marker expressed by rat osteoblasts and osteocytes.

A new marker for cells of the osteoblastic lineage was identified by raising monoclonal antibodies against an immortalized rat osteoblastic cell line. Among the different antibodies one was selected which, on tissue sections, strongly reacts with osteoblasts, preosteocytes, and osteocytes. This antibody, designated E11, recognizes an antigen localized at the cell surface. The cDNA encoding the E11 antigen was cloned from a cDNA library prepared from ROS 17/2.8 cells, using a eukaryotic expression system. The E11 cDNA sequence revealed homology with the murine OTS-8/gp38 sequence. In situ hybridization confirmed that E11 mRNA expression in bone is restricted to osteoblasts and osteocytes. The tissue specificity of the E11 expression was studied by immunohistochemistry and Northern blot analysis. Apart from bone, E11-positive cells were also found in lung: namely, the alveolar cells of type I. Epithelial cells of the choroid plexus and endothelial cells of lymphatic vessels were also labeled with mAb E11. These results were confirmed by Northern blot, as the 1.8 kb E11 mRNA transcript was detected in bone and also in lung, brain, and skin. In conclusion, we describe a novel osteoblastic product which is expressed by mature osteoblasts and newly formed osteocytes.

Adenylyl Cyclases↗
PubMed1996

Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption.

Current knowledge indicates that osteoblasts play an integral role in osteoclastic bone resorption through an osteoclast-stimulating activity produced by osteoblasts in response to resorption-promoting osteotropic factors. Previously, we have shown that the inhibitory action of the bisphosphonates on bone resorption in part is mediated by osteoblasts. The aim of the present study was to investigate whether the bisphosphonate-generated inhibition is due to these compounds decreasing the synthesis of the osteoclast-stimulating activity or is the result of osteoblasts synthesizing an osteoclast resorption inhibitor. Using the osteoblastic cell line CRP 10/30, which produces osteoclast- stimulating activity, constitutively and employing isolated rat osteoclasts cultured on ivory, evidence was obtained indicating that the bisphosphonates ibandronate and alendronate at a concentration of 10(-7) M induce osteoblasts to synthesize an osteoclast inhibitor that reduces pit formation by more than 50%. The inhibitor is heat and proteinase labile and has a molecular mass between 1-10 kDa. The reduction of resorption pits is paralleled by a decrease in tartrate-resistant acid phosphatase-positive mono- and multinucleated cells, whereas the mean area resorbed per pit was not changed, suggesting that the inhibitor affects osteoclast formation and/or survival and probably not the osteoclast resorption activity. Rat preosteoblastic cells and rat dermal fibroblasts were found not to produce the inhibitor. In conclusion, osteoblasts aside from their role of mediating osteoclastic resorption promoters are also involved in inhibiting bone resorption through the synthesis of an osteoclast resorption inhibitor.

Acid Phosphatase↗
PubMed1995

Downregulation of colony-stimulating factor-1 (CSF-1) binding by CSF-1 in isolated osteoclasts.

Colony-stimulating factor-1 (CSF-1), also called macrophage colony-stimulating factor, is the growth factor for the cells of the mononuclear phagocytic system. Furthermore, CSF-1 is essential in osteoclastogenesis and also affects mature osteoclasts. The receptor for CSF-1 was demonstrated on cells of the osteoclast lineage, with highest levels on the mature cells. This study investigated whether the binding of CSF-1 to isolated rat osteoclasts is modulated by the growth factor itself. Exposure of osteoclasts to CSF-1 for 1 hour virtually abolished binding of the growth factor. After removal of CSF-1, binding sites were restored within 4 hours. This recovery was blocked by cycloheximide, indicating the dependence on new protein synthesis for reexpression of receptors on the cell surface. The observed downregulation of CSF-1 binding sites might be a mechanism to control the effects of the growth factor on mature osteoclasts.

Animals↗
PubMed1995

The food-induced stimulation of bone resorption in the rat, assessed by the urinary [3H]-tetracycline excretion, is mediated by parathyroid hormone.

Using the urinary excretion of [3H]-tetracycline from prelabeled rats to monitor bone resorption, we have previously shown that food intake is associated with a rapid and large increase in bone resorption. This increase is blunted when the daily intake is fractionated into 4 portions instead of being given at once. Food fractionation also leads to a large increase in bone mass. In order to establish whether the thyroparathyroid gland is involved in this effect, thyroparathyroidectomized (TPTX) rats were studied. The food-induced increase in bone resorption was absent in TPTX rats. Therefore, the pattern of parathyroid hormone (PTH) was investigated during the development of the food-induced bone resorption, and under food fractionation. Rats were trained to eat their daily high Ca food in less than two hours. Thereafter they were given food portions of 5 or 20 grams, respectively. PTH in serum was measured at 0, 1, 2, 3, and 4 hours after food intake. In rats given the large food portions, a conspicuous increase of PTH was found. In contrast, serum PTH of rats fed the small food portion did only change to an insignificant extent. This study in rats shows that the ingestion of a large meal induces a transient increase of PTH. The present results can therefore explain the formerly observed acute increase in bone resorption following food intake and its blunting by food fractionation. It is not known, whether such a mechanism occurs also in humans. If so, these results would provide the rational basis to decrease bone resorption by food fractionation.

Animals↗