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PubMedDate not supplied

Inhibition of bone resorption by difluoromethylene diphosphonate in organ culture.

A newly synthesized diphosphonate, difluoromethylene diphosphonate (F2MDP), was studied for its effects on bone resorption, as measured by the release of previously incorporated 45Ca. F2MDP (10 microM to 1000 microM) effectively inhibited both unstimulated and parathyroid hormone-stimulated resorption, and the amount of 45Ca release decreased with time. Dichloromethylene diphosphonate (Cl2MDP) and ethane-1-hydroxyl-1, 1-diphosphonate (EHDP) inhibited resorption to similar extents with two exceptions: At concentrations of 10 microM and 100 microM, F2MDP was more effective than EHDP and less effective than Cl2MDP. No greater inhibition was observed when bones had been stimulated with PTH prior to the addition of F2MDP. In addition, bones treated with F2MDP only during the first half of the incubation period exhibited reductions in the amount of 45Ca released during the second half similar to that observed when F2MDP was continuously in the medium, indicating a prolonged effect. Morphologic alterations of osteoclasts suggestive of cell degeneration were observed in F2MDP-treated bones, which were similar to those observed in bones treated with Cl2MDP and EHDP. Due to the presence of fluorine, F2MDP may be useful as an experimental tool to investigate the mode of action of all diphosphonates, in addition to its possible use as a therapeutic agent for diseases of increased bone resorption.

Animals↗

PubMed1988

Rapid and precise micro-methods for quantitating active components in commercial bone scintigraphy kits--II. Diphosphonates.

Two parallel, independent micro-methods for diphosphonate determination are presented. These procedures are based on the interference of diphosphonate with the formation of cation-morin (3,5,7,2',4'-pentahydroxyflavone) complexes. In the spectrophotometric method, a change of the absorbance of thorium-morin complex is used as a measure of diphosphonate concentration. In the fluorimetric method, a decrease of the fluorescence of aluminium-morin complex is used. Both methods: (1) quantitate methylene-diphosphonate in the range of 5-40 x 10(-9) M with a coefficient of variation of less than 1%; (2) are specific and interference-free in commercial kits control; (3) are operative with other diphosphonates; and (4) are adaptable to the analysis of chromatographic eluents.

Bone and Bones↗

PubMed1981

The influence of 1-hydroxyethane-1,1-diphosphonate and dichloromethanediphosphonate on lysine hydroxylation and cross-link formation in rat bone, cartilage and skin collagen.

The effects in vivo of dichloromethanediphosphonate and 1-hydroxyethane 1,1-diphosphonate on collagen solubility, hydroxylation of lysine and proline and on the formation of collagen intermolecular cross-links were studied by using rat bone, cartilage and skin tissues. Dichloromethanediphosphonate decreased bone collagen solubility both in acetic acid and after pepsin treatment. Although none of the diphosphonates had any effect on the hydroxylation of proline, dichloromethane-diphosphonate, but not 1-hydroxyethane-1,1-diphosphonate, increased the number of hydroxylysine residues in the alpha-chains of bone, skin and cartilage collagen. The stimulatory effect was dose-dependent. The dichloromethanediphosphonate-mediated increase in hydroxylysine residues in bone and cartilage was manifested in an increase of dihydroxylysinonorleucine, the cross-link that is formed by the condensation of two hydroxylysine residues. The cross-link hydroxylysinonorleucine, a condensation product of hydroxylysine and lysine, on the other hand, was decreased. The total number of intermolecular cross-links was not changed by the diphosphonate.

Animals↗

PubMed1995

Inhibition of streptococcal growth, F-ATPase and pyrophosphatase by diphosphonates.

1-Hydroxyethane-1,1-diphosphonate (EHDP) and a variety of other diphosphonates, and also pyrophosphate, at millimolar levels were found to inhibit the growth of Streptococcus mutans GS-5. Inhibition appeared to be due mainly to chelation of Mg2+ and could be readily reversed through addition of Mg2+, or less effectively, by other divalent cations. The trianionic forms of the diphosphonates or pyrophosphate were more effective inhibitors than the dianionic forms. Diphosphonates and pyrophosphate did not inhibit glycolysis by S. mutans, assayed in terms of glucose utilization, or arginolysis by Streptococcus rattus FA-1, assayed in terms of ammonia production. However, they did act as buffers to moderate pH changes. Diphosphonates also were inhibitors of the F-ATPase of S. mutans by complex mechanisms only partly reversible with divalent cations. They also were inhibitors of the pyrophosphatase of the organism. However, intact cells were impermeable to the compounds, and inhibition of cytoplasmic or membrane enzymes did not appear to be involved in growth inhibition.

Cell Membrane Permeability↗

PubMed2003

Immediately loaded bar-connected implants with an anodized surface inserted in the anterior mandible in a patient treated with diphosphonates for osteoporosis: a case report with a 12-month follow-up.

BACKGROUND: It has been suggested that tooth loss is greater in the osteoporotic patient population. Only a few cases have been reported in the literature about the use of dental implants in patients with osteoporosis. Diphosphonates are stable analogs of pyrophosphate, a physiologic regulator of calcification and bone resorption. Multiple implant failures have been reported in a patient undergoing treatment with diphosphonates. Recently, several clinical and experimental reports have shown that immediate loading of dental implants is possible in selected situations. PURPOSE: The aim of this case report was to present the clinical outcome of immediate loading of implants in a patient undergoing diphosphonate treatment for osteoporosis. MATERIALS AND METHODS: In a 65-year-old patient undergoing diphosphonate treatment for osteoporosis, four implants were inserted in the anterior mandible. The implants were connected with a bar supporting an overdenture and were then loaded the same day. RESULTS: No problems occurred in the postoperative period. At 1-year follow-up, all four of the implants appeared to be clinically osseointegrated, and no mobility was present. Minimal bone resorption was present around all implants. CONCLUSIONS: Our case report points to the fact that, contrary to what has been reported in the literature, it is possible to successfully insert and load immediately after surgery dental implants in a patient undergoing diphosphonate treatment for osteoporosis.

Aged↗

PubMed1987

Comparative effects of intravenous diphosphonates on calcium and skeletal metabolism in man.

We have assessed the early effects of three diphosphonates on calcium and skeletal homeostasis in 68 patients with Paget's disease of bone treated with daily intravenous infusions for five consecutive days. Both clodronate (300 mg/day) and aminohexane diphosphonate (AHDP; 50 mg/day) induced a fall in serum and urine calcium, and secondary hyperparathyroidism. In contrast, these changes were not observed with etidronate (300-700 mg/day) despite similar effects on bone resorption, as judged by urinary excretion of hydroxyproline with each of the three disphosphonates. Histological studies during the early phase of treatment indicated that etidronate, but not clodronate or AHDP, acutely impaired the accretion of calcium into bone, thereby offsetting a hypocalcaemic response. All three diphosphonates induced significant increases in plasma phosphate and tubular reabsorption of phosphate (TmP/GFR). The increase induced by etidronate remained significantly higher than pretreatment values for one month, whereas those induced by clodronate and AHDP were less marked and ill-sustained, and followed by significant decreases in both measurements. These data indicate that the effects of different diphosphonates on serum calcium homeostasis are heterogeneous, depending not only on the prevailing rate of bone resorption, but also on the rate of bone formation, and the effect of each diphosphonate on bone and mineral accretion.

Alkaline Phosphatase↗

PubMedDate not supplied

[Effect of diphosphonates on the development of osteoporosis in the hypokinetic rat].

Using histomorphometric methods, the effect of diphosphonates (hydroxydimethylaminopropylene diphosphonic acid and hydroxyethylene diphosphonic acid) on the development of osteoporosis in spongy matter of tibia and vertebrae of the rats exposed to hypokinesia for 60 days was investigated. It was found that aminopropylene diphosphonic acid in the dose 6 mg phosphorus/kg/day prevented osteoporosis and caused an increase in the volume density and abnormal (cartilage rich and poorly ossified) spongy bone. By contrast, ethylene diphosphonic acid in the dose 9 mg phosphorus/kg/day did not prevent osteoporosis but reduced its severity.

Animals↗

PubMed1984

Inhibition by diphosphonates of bone resorption induced by the Walker tumor of the rat.

An animal model is described to test the effect of diphosphonates, which are powerful antiosteolytic agents, against bone tumors. This model consists of injecting Walker tumor cells into one iliac artery of a series of rats while the contralateral artery is clamped during the injection, and waiting 7 days to obtain a significant destruction of the femur and tibia of the rats. In most of the animals, after this delay, extensive lesions are observed macroscopically by X-ray and histologically. The parenteral administration of three diphosphonates, dichloromethylene diphosphonate, ethanehydroxydiphosphonate , and aminopropanediphosphonate , at 16 and 160 mumol/kg/day, protects the bones by decreasing the extent of osteolysis. This protective effect is seen both in the tumor-injected leg and in the contralateral leg and is significant when compared to nontreated animals. The most active of the drugs was dichloromethylene-diphosphonate; ethanehydroxydiphosphonate and aminopropanediphosphonate were less active, especially when given at the higher dosage. All diphosphonates produce a marked decrease of the number of osteoclasts; ethanehydroxydiphosphonate at the higher dosage, induced a large increase of nonmineralized bone. These results are discussed in light of recent clinical work, showing that this animal model is a useful tool to test the effect of new drugs against osteolysis of cancer.

Animals↗

PubMed1980

Comparative evaluation of three diphosphonates: in vitro adsorption (C- 14 labeled) and in vivo osteogenic uptake (Tc-99m complexed).

We have investigated the in vitro adsorption of three C-14-labeled diphosphonates on calcium phosphate. The three are 1-hydroxy[1-14C]ethylidene diphosphonate (C-14 HEDP), [14C]methylenediphosphonate (C-14 MDP), and hydroxy[14C]methylenediphosphonate (C-14 HMDP). All three adsorbed significantly more, per mole of calcium, on amorphous calcium phosphate than on crystalline hydroxyapatite. Among the three diphosphonates, C-14 HMDP adsorbed--on both amorphous and crystalline calcium phosphate--to a greater degree than did the other two bone-seeking agents. Moreover, when HMDP was complexed with Sn(II) and Tc-99m, it produced a significantly higher uptake of Tc-99m, per mg of calcium, in an isolated in vivo site of osteogenesis. The mechanisms of adsorption are discussed relative to the hydroxyl group on the diphosphonate, to the solubility of the calcium salts to the diphosphonates, and to the form of the calcium phosphate. These studies form a working rationale for the clinically observed high contrast obtained with Tc-99m HMDP between normal bone and soft tissue, and between normal and abnormal bone.

Adsorption↗

PubMed1983

[Inhibition of bone tissue formation by propane-2,2-diphosphonate].

Among other diphosphonates here described propane-2,2-diphosphonate displays specific effects on bone-turnover. In contrast to other diphosphonates propane-2,2-diphosphonate inhibits especially different enzymes of growing bone and therefore inhibits formation of bone. The indication for the clinical use follows from that effect: pathologic states with increased bone formation may be treated by application of propane-2,2-diphosphonate.

Animals↗

PubMed1991

Estrogen and diphosphonate treatment provide long-term protection against osteopenia in ovariectomized rats.

The goal of this study is to determine whether the previously observed, short-term protective effect of estrogen and diphosphonate compounds against osteopenia in ovariectomized (OVX) rats can be maintained for an entire year. Sham-operated control and OVX rats were treated intermittently with vehicle alone, estrogen, or the diphosphonate compounds etidronate disodium (EHDP) and risedronate (NE-58095) for 360 days after surgery. Their proximal tibiae and first lumbar vertebrae were processed undecalcified for quantitative bone histomorphometry. Both skeletal sites in vehicle-treated OVX rats were characterized by decreased cancellous bone volume and increases in most cellular and fluorochrome-based indices of bone formation and resorption. Treatment of OVX rats with estrogen or diphosphonate compounds depressed bone turnover and provided nearly complete protection against cancellous bone loss. Long-term EHDP treatment induced a moderate mineralization defect, as indicated by increased absolute osteoid volume and a high proportion of osteoid surfaces devoid of adjacent osteoblasts. In contrast, NE-58095 had minimal effects on bone mineralization. These findings indicate that diphosphonate compounds and estrogen provide long-term protection against tibial and vertebral osteopenia in OVX rats. They further indicate that diphosphonate compounds merit consideration as an alternative to estrogen for the prevention of postmenopausal bone loss.

Animals↗

PubMed1993

Skeletal effects of withdrawal of estrogen and diphosphonate treatment in ovariectomized rats.

The study was designed to determine the skeletal effects of withdrawal of estrogen and diphosphonate treatment in the estrogen-deplete state. Groups of ovariectomized (OVX) rats were treated with vehicle alone, estrogen, or the diphosphonates etidronate or risedronate for a 180-day period. A group of sham-operated control rats was treated for 180 days with vehicle alone. All treatments were then terminated, followed by sequential sacrifice of rats at 0, 35, 90, 180, and 360 days after withdrawal of treatment. The proximal tibia from each animal was processed undecalcified for quantitative bone histomorphometry. At the end of the treatment period, vehicle-treated OVX rats were characterized by cancellous osteopenia and increased bone turnover relative to vehicle-treated control rats. Treatment of OVX rats with estrogen or diphosphonates depressed bone turnover and protected against cancellous osteopenia. During the withdrawal period, OVX rats previously treated with estrogen exhibited rapid bone loss associated with increased bone turnover. The bone protective effect of the hormone in OVX rats was nearly completely lost by 90 days of withdrawal. In contrast, OVX rats maintained low levels of bone turnover and normal cancellous bone mass at 180 days of withdrawal from diphosphonate treatment. The results suggest that estrogen-deplete women who are withdrawn from estrogen replacement are at high risk for subsequent bone loss. They further suggest that widely spaced periods of intermittent diphosphonate treatment may be sufficient to prevent the development of osteopenia in postmenopausal and oophorectomized women.

Animals↗

PubMed2003

Synthesis and characterization of three novel cation-containing (NH4+/C3H7NH3+/NH3+C2H4NH3+) aluminum diphosphonates.

Three new aluminum diphosphonates (C(3)H(7)NH(3))[AlF[(HO)O(2)PC(2)H(4)PO(3)]] (1) (orthorhombic, Pnma, a = 8.2048(1) A, b = 6.90056(6) A, c = 19.6598(4) A, Z = 4), (H(3)NC(2)H(4)NH(3))[Al(OH)(O(3)PC(2)H(4)PO(3))] (2) (monoclinic, P2(1)/n, a = 11.142(3) A, b = 7.008(2) A, c = 12.903(5) A, beta = 96.24(7) degrees, Z = 4), and (NH(4))(2)[AlF(O(3)PCH(2)PO(3))] (3) (orthorhombic, Cmcm, a = 16.592(2) A, b = 7.5106(9) A, c = 7.0021(9) A, Z = 4) have been synthesized by solvothermal methods in the presence of linear organic ammonium cations (for 1 and 2) and ammonium cations (for 3) and their structures determined using powder, microcrystal, and single-crystal X-ray diffraction data, respectively. All three materials contain a similar one-dimensional chain motif which is related to that found in the mineral Tancoite. This chain motif consists of corner-sharing octahedra (AlO(4)F(2) for 1 and 3 and AlO(6) for 2) linked together through the bridging CPO(3) tetrahedra of the diphosphonate groups. These chains are unusual in that each diphosphonate moiety acts as a bisbidentate ligand that is coordinated to the same two metal centers through both of the O(3)PC- groups of the diphosphonate ligand. The arrangement of the Tancoite-like chains and charge compensation cations in the structures of compounds 1-3 is seen to be dependent upon the nature of the diphosphonic acid and organoammonium/ammonium cations. Careful selection of these two components may provide a method to design future materials in this system.

Journal Article↗

PubMed1975

Renal secretion of diphosphonates in rats.

Diphosphonates, characterized by a P--C--P bond, are relatively new experimental drugs used for the treatment of myositis ossificans, dental calculus, nephrolithiasis and Paget's disease. These compounds are not metabolized and the fraction which is not taken up by the skeleton is excreted unchanged in the urine. In the present study, the renal clearances of two 14C-labelled diphosphonates, disodium ethane-1-hydroxy-1,1-diphosphonate (CEHDP) and disodium dichloromethylene diphosphonate (CC12MDP) have been measured in conscious rats. The clearances have been found to be higher than the glomerular filtration rate (GFR), Cdiphosphonate/GFR being about 1.5. This observation indicates net tubular secretion of both drugs. High plasma concentration of EHDP or Cl2MDP significantly depressed CEHDP, whereas CEHDP was not influenced by varying urine pH, by infusing NH4Cl or NaHCO3, or by simultaneous administration of high doses of para-aminohippurate (PAH), probenecid, N-methylnicotinamide or Ca-EDTA. High plasma concentration of inorganic phosphate depressed CEHDP and also depressed the in vitro ultrafiltrability of EHDP. In conclusion, these results provide evidence of an active renal transport of diphosphonates which appears distinct from the mechanisms handling organic acids, organic bases and EDTA in the rat kidney.

Aminohippuric Acids↗

PubMed1981

Effects of thyroparathyroidectomy, phosphate depletion and diphosphonate therapy on acute uraemic extra-osseous calcification in the rat.

1. The effects of acute uraemia on arterial and visceral calcium concentrations were studied in acutely uraemic rats. The influences of thyroparathyroidectomy, phosphate depletion and diphosphonate therapy on extra-osseous calcium concentrations were assessed in this model. 2. Aortic and visceral calcium concentrations were greater in acutely uraemic rats than in non-uraemic rats. Both prior thyroparathyroidectomy and prior phosphate-depletion resulted in lower aortic and visceral calcium concentrations in non-uraemic rats and prevented the increase in aortic and visceral calcium concentrations with acute uraemia. Diphosphonate given for 5 days before and for 2 days after the induction of acute uraemia resulted in lower tissue calcium concentrations than in non-diphosphonate-treated acutely uraemic rats. In contrast, diphosphonate given only immediately before or only after induction of acute uraemia did not prevent the increase in extra-osseous calcium concentrations with acute uraemia. 3. It is concluded that acute uraemia results in an increase in arterial and visceral calcium concentrations. Both thyroparathyroidectomy and phosphate depletion are effective in preventing the increase in extra-osseous calcium concentrations in acute uraemia. Diphosphonates may have a future role in preventing such calcification.

Animals↗

PubMed1979

Comparative antiinflammatory and bone protective effects of two diphosphonates in adjuvant arthritis.

The effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethane diphosphonate (Cl2MDP) were evaluated in the rat adjuvant model of arthritis to directly compare their ability to inhibit arthritic processes. The results of the experiment indicated that both diphosphonates inhibited osseous changes, pedal inflammation, and the change in body weight gain patterns which are characteristic of this model. The latter effects suggest that diphosphonates may have antinflammatory activity that is not related to their previously known actions on bone. Cl2MDP appeared to be more effective than EHDP in this particular model when all aspects were considered. The relationship of these results to the potential safety of these compounds in clinical situations is discussed.

Animals↗

PubMed1980

Diphosphonates inhibit bone resorption by macrophages in vitro.

The diphosphonates are a group of synthetic compounds which are adsorbed onto hydroxyapatite crystal surfaces and inhibit both the growth and dissolution of these crystals. They also inhibit mineralisation and resorption of bone in vivo. The effects of diphosphonates were tested on the attachment of macrophages to bone and on the dissolution of bone mineral by macrophages. Attachment was unaffected but resorption was inhibited. Diphosphonates were found to be cytotoxic at much lower concentrations when bone mineral was present, and the most likely explanation for the effects of diphosphonate on bone resorption is that the drug is adsorbed onto the mineral surface where it reaches cytotoxic concentrations.

Animals↗

PubMed1982

Diphosphonate bone scanning agents--current concepts.

The bone scan is generally recognized to be an extremely powerful investigational tool in the evaluation of patients with skeletal disease. Currently 99mTc-methylene diphosphonate is the most widely used bone scanning agent, but recently several new diphosphonate compounds have been introduced which appear to have relatively higher skeletal affinity, leading to greater absolute uptake of tracer by bone. While the resulting improved contrast between bone and background soft-tissue may provide more pleasing scan images, it is not clear that increased bone uptake of tracer is equally desirable for identification of disease. Nevertheless, to date, no significant difference in lesion detection has been found in any comparative study of diphosphonate compounds. In this review the clinical studies evaluating diphosphonate bone scanning agents are summarized and the properties required of an ideal bone scanning agent in both benign and malignant disease discussed.

Bone Diseases↗