Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo.
19 Sep 1969-Science (American Association for the Advancement of Science)-Vol. 165, Iss: 3899, pp 1262-1264
TL;DR: Two diphosphonates containing the P-C-P bond retard the rate of dissolution of apatite crystals in vitro and inhibit bone resorption induced by parathyroid extract in mouse calvaria in tissue culture and in thyroparathyroidectomized rats in vivo.
Abstract: Two diphosphonates containing the P-C-P bond, Cl(2)C(PO(3)HNa)(2), and H(2)C(PO(3)HNa)(2) retard the rate of dissolution of apatite crystals in vitro. They inhibit bone resorption induced by parathyroid extract in mouse calvaria in tissue culture and in thyroparathyroidectomized rats in vivo.
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TL;DR: Each bisphosphonates has a unique profile that may help to explain potential clinical differences among them, in terms of their speed and duration of action, and effects on fracture reduction.
Abstract: Summary
Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness.
1,280 citations
Cites background from "Diphosphonates inhibit hydroxyapati..."
...The observation that BPs have the novel property of being able to inhibit the dissolution of hydroxyapatite (HAP) crystals [7–9], as had already been shown for pyrophosphate (PPi) [10], led to studies demonstrating that BPs also inhibited bone resorption in many different experimental models [3]....
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TL;DR: A comparison study of the effects of calcification, bone resorption, and other effects on bone formation and noncalcified tissues in animals and humans using a model derived from animal toxicology and human adverse events.
Abstract: I. Introduction II. Chemistry III. Effects in Vivo A. Inhibition of calcification B. Inhibition of bone resorption C. Effects on bone formation D. Effects on noncalcified tissues IV. Mechanisms of Action A. Calcification B. Bone resorption C. Other effects V. Pharmacokinetics VI. Animal Toxicology and Human Adverse Events A. Animal toxicology B. Human adverse events VII. Conclusion
1,183 citations
TL;DR: This review will deal with the mechanisms of action of bisphosphonates and in vitro results, as well as results both in animals and humans, will be integrated in an attempt to deduce the current state of the art.
Abstract: Because of its failure to act when given orally and its rapid hydrolysis when given parenterally, pyrophosphate was used therapeutically only in scintigraphy and against dental calculus. This prompted us to search for analogs that showed similar physicochemical activity but resisted enzymatic hydrolysis and, therefore, would not be degraded metabolically. The bisphosphonates fulfilled these conditions. This review will deal with the mechanisms of action of these compounds. In vitro results, as well as results both in animals and humans, will be integrated in an attempt to deduce the current state of the art. Various reviews have been published recently on bisphosphonates and may be consulted also for information on other aspects (8 ‐14). Since the literature in this field is plentiful, selective citation was necessary. Priority is given to papers dealing with the mechanisms of action. Since many papers often deal with the same finding, in most cases only the first ones are quoted. Subsequent papers are quoted only if they convey new knowledge.
1,087 citations
Cites background from "Diphosphonates inhibit hydroxyapati..."
...Bisphosphonates, like pyrophosphate, do indeed inhibit mineral dissolution (7, 60, 61, 136)....
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...This is explained by the fact that hypercalcaemia is often due to the systemic production of PTH-related peptide, which increases both bone resorption and tubular reabsorption of calcium (89), with bisphosphonates acting only on the former....
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...They impair resorption induced by agents such as PTH (60, 61), 1,25-(OH)2 vitamin D, and retinoids....
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...Bisphosphonates also delay the dissolution of calcium phosphate crystals (60, 61, 136)....
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...Bisphosphonates block bone resorption induced by various means in organ culture (60, 61, 103, 104)....
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TL;DR: Findings suggest that alendronate binds to resorption surfaces, is locally released during acidification, the rise in concentration stops resOrption and membrane ruffling, without destroying the osteoclasts.
Abstract: Studies of the mode of action of the bisphosphonate alendronate showed that 1 d after the injection of 0.4 mg/kg [3H]alendronate to newborn rats, 72% of the osteoclastic surface, 2% of the bone forming, and 13% of all other surfaces were densely labeled. Silver grains were seen above the osteoclasts and no other cells. 6 d later the label was 600-1,000 microns away from the epiphyseal plate and buried inside the bone, indicating normal growth and matrix deposition on top of alendronate-containing bone. Osteoclasts from adult animals, infused with parathyroid hormone-related peptide (1-34) and treated with 0.4 mg/kg alendronate subcutaneously for 2 d, all lacked ruffled border but not clear zone. In vitro alendronate bound to bone particles with a Kd of approximately 1 mM and a capacity of 100 nmol/mg at pH 7. At pH 3.5 binding was reduced by 50%. Alendronate inhibited bone resorption by isolated chicken or rat osteoclasts when the amount on the bone surface was around 1.3 x 10(-3) fmol/microns 2, which would produce a concentration of 0.1-1 mM in the resorption space if 50% were released. At these concentrations membrane leakiness to calcium was observed. These findings suggest that alendronate binds to resorption surfaces, is locally released during acidification, the rise in concentration stops resorption and membrane ruffling, without destroying the osteoclasts.
1,017 citations
Cites background from "Diphosphonates inhibit hydroxyapati..."
...Osteoclasts from adult animals, infused with parathyroid hormone-related peptide (1-34) and treated with 0....
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...Some bisphosphonates also reduce bone resorption (31); however, this effect cannot be attributed to the reduction in mineral solubility since the potency of various bisphosphonates in the two assays varies considerably (58)....
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...Bisphosphonate inhibition of bone resorption was initially attributed to reduced hydroxyapatite dissolution (31); however, structure-activity relation studies showed no close correlation between the two actions and directed attention to their effects on bone cells (1)....
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...Distal tibiae of adult rats infused with PTHrP (1-34) NH2given a therapeutic dose of 0....
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...Bisphosphonates are nonhydrolyzable analogues of pyrophosphate, which reduce the dissolution rate of the bone mineral hydroxyapatite (31)....
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TL;DR: Bisphosphonates currently are the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor‐associated osteolysis and hypercalcemia, Paget's disease, and osteoporosis.
Abstract: BACKGROUND
Bisphosphonates currently are the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor-associated osteolysis and hypercalcemia, Paget's disease, and osteoporosis. These compounds have high affinity for calcium and therefore target to bone mineral, where they appear to be internalized selectively by bone-resorbing osteoclasts and inhibit osteoclast function.
METHODS
This article reviews the pharmacology of bisphosphonates and the relation between the chemical structure of bisphosphonates and antiresorptive potency, and describes recent new discoveries of their molecular mechanisms of action in osteoclasts.
RESULTS
Bisphosphonates can be grouped into two pharmacologic classes with distinct molecular mechanisms of action. Nitrogen-containing bisphosphonates (the most potent class) act by inhibiting the mevalonate pathway in osteoclasts, thereby preventing prenylation of small GTPase signaling proteins required for osteoclast function. Bisphosphonates that lack a nitrogen in the chemical structure do not inhibit protein prenylation and have a different mode of action that may involve the formation of cytotoxic metabolites in osteoclasts or inhibition of protein tyrosine phosphatases.
CONCLUSIONS
Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts. After more than 30 years of clinical use, their molecular mechanisms of action are only just becoming clear. Cancer 2000;88:2961–78. © 2000 American Cancer Society.
916 citations
References
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TL;DR: Two diphosphonates containing the P-C-P bond inhibit the crystallization of calcium phosphate in vitro and prevent aortic calcification of rats given large amounts of vitamin D3.
Abstract: Two diphosphonates containing the P-C-P bond, CH(3)C(OH)(PO(3)HNa)(2) and H(2)C(PO(3)HNa)(2), inhibit the crystallization of calcium phosphate in vitro and prevent aortic calcification of rats given large amounts of vitamin D(3). The diphosphonates therefore have effects similar to those described for compounds containing the P-O-P bond but are active when administered orally.
588 citations
478 citations
TL;DR: The nucleating properties of various collagens have been tested by determining quantitatively the minimum ion product, Ca times P, required to form calcium phosphate crystals.
Abstract: The nucleating properties of various collagens have been tested by determining quantitatively the minimum ion product, Ca times P, required to form calcium phosphate crystals. While most collagens ...
410 citations
TL;DR: This work showed plasma to contain one or several substances highly inhibitory to apatite precipitation, and suggested this inhibitor to be a polyphosphate, but to the knowledge, no such compound has so far been demonstrated in plasma or in urine.
Abstract: THE mechanism of calcification has been considerably clarified recently1. Collagen fibrils were shown to possess in vitro the property of nucleating hydroxyapatite precipitation and of triggering mineralization1–3. But why does only part of the collagen present in the organism calcify ? Recently, we suggested that the activating sites of collagen and crystal growth could be blocked in the organism by a plasma inhibitor4. Indeed we showed plasma to contain one or several substances highly inhibitory to apatite precipitation. The technique used was to determine in vitro, at physiological conditions, the minimum ion product (Ca) × (P) necessary for hydroxyapatite precipitation. After addition of plasma, the rise of this minimum product revealed the presence of inhibitors. As the inhibitor was shown to be destroyed by alkaline phosphatase, and the polyphosphates to have a strong inhibitory activity at concentrations as low as 10−7 M, we suggested this inhibitor to be a polyphosphate. However, to our knowledge, no such compound has so far been demonstrated in plasma or in urine.
238 citations