Marion D. Francis

Bio: Marion D. Francis is an academic researcher from Procter & Gamble. The author has contributed to research in topics: Calcium & Fluoride. The author has an hindex of 23, co-authored 56 publications receiving 3046 citations. Previous affiliations of Marion D. Francis include Norwich University.

Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and 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.

Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo.

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.

The inhibition of calcium hydroxypatite crystal growth by polyphosphonates and polyphosphates.

Abstract: The formation of crystalline calcium hydroxyapatite from solutions of calcium and phosphate ions and the inhibition of calcium hydroxyapatite crystal growth by polyphosphonates and polyphosphates have been studied. The polyphosphonates, disodium ethane-1-hydroxy-1,1-diphosphonate and disodium dichloromethane diphosphonate, are effective inhibitors of calcium hydroxyapatite crystal growth. The polyphosphates are also effective inhibitors of calcium hydroxyapatite crystal growth as long as the required level of intact polyphosphate is present in the system. However, because of their hydrolytic instability, which is enhanced by high temperature, low pH, and certain enzymes, the concentration of the polyphosphate decreases with timein vitro, and its activity as an inhibitor is lost. In contrast to the polyphosphates, the polyphosphonates are hydrolytically stable. The polyphosphonates are chemisorbed on the surface of the microcrystallites of calcium hydroxyapatite and, in the manner of other known crystal growth poisons, thus prevent further crystal growth. The stability of the polyphosphonates and their chemisorption on apatite suggest their use in medical and dental applications involving pathological calcium and phosphate metabolism.

Hydroxyapatite formation from a hydrated calcium monohydrogen phosphate precursor.

Abstract: Hydrated calcium monohydrogen phosphate is proposed as the logical precursor in the formation of hydroxyapatite and a unifying theory for the formation of low calcium, or defect apatites, is presented. Structural relationships between calcium monohydrogen phosphate dihydrate and hydroxyapatite indicate that either material can provide the atomic arrangment for the epitaxial growth of one on the other. The formation of apatite is presented as the summation of two rate processes: the initial fast formation of amorphous calcium monohydrogen phosphate dihydrate and the subsequent slow formation of crystalline hydroxyapatite from the initial precipitate. Ca/P ratios of calcium phosphates, formed from compositions in the phase region of hydroxyapatite as a function of time, suggest a varying composition of calcium monohydrogen phosphate dihydrate and hydroxyapatite. Hydrated calcium monohydrogen phosphate is proposed on the basis of rate and composition of calcium phosphate formed and on crystallographic data to be a necessary seed for growth of hydroxyapatite in bone and teeth at physiological pH.

Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue

Abstract: Compositions for inhibiting anomalous deposition and mobilization of calcium phosphates in animal tissue, comprising an effective amount of an alkali metal, ammonium or substituted ammonium carbonyldiphosphonate in a pharmaceutical carrier; and a method for treating conditions involving pathological calcification and hard tissue demineralization in an animal comprising administering to such animal said compositions.

Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy

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.

Bisphosphonates: Mechanisms of Action

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

Bisphosphonates: mechanisms of action.

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.

Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure.

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.

Cellular and molecular mechanisms of action of bisphosphonates

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.