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PubMedDate not supplied

[Effect of inorganic pyrophosphate and its diphosphonate analogs on glucose-6-phosphatase dehydrogenase activity of mouse organs].

The glucose-6-phosphatase dehydrogenase (EC 1.1.1.49) reaction of mouse organs was studied as affected by PPi and its diphosphonate analogs. It is shown that in vitro and hydroxy-1-ethane-1,1-diphosphonic acid) inhibit the mentioned enzyme of the mouse spleen and liver. The effect of hydroxyl-1-ethane-1,1-diphosphonic acid was used as an example to show that inhibition of glucose-6-phosphate dehydrogeanse by diphosphonates belongs to the mixed type characterized by changes in the Km and Vmax values. For the spleen enzyme Km equals 0.064 mM, Vmax - 4.7 Mg of NADPH per 1 mg of protein-1. h-1. Administration of methylene diphosphonic acid causes an inhibition in vivo of the glucose-6-phosphatase dehydrogenate activity of the liver but not of the spleen and thymus. Basing on the isoenzymic composition of the enzyme for the mentioned organs, it is possible to suppose that the difference in the methylene diphosphonic acid effect in the liver and lymphoid organs may depend on the differences in its isoenzymic spectrum. The fact that in vivo methylene diphosphonic acid in a dose having an immuno-depressive action has no influence on the activity of glucose-6-phosphatase dehydrogenase in the lymphoid organs, may evidence for the absence of the indirect immunodepressive effect of diphosphonate by affecting this enzyme.

Animals↗

PubMed1999

Comparison of various rhenium-188-labeled diphosphonates for the treatment of bone metastases.

In the past, many diphosphonates were introduced as bone scan radiopharmaceuticals. In addition, diphosphonates have been labeled with beta-emitted isotopes and developed into useful therapeutic drugs for bone metastases. However, it is not clear which diphosphonate is the best choice when labeling with Re-188. In this study, we labeled methylene diphosphonate (MDP), hydroxyethylidene diphosphonate (HEDP), and hydroxymethane diphosphonate (HDP) with Re-188. Each radiopharmaceutical was further evaluated in two conditions (with and without carrier). Twenty-four rabbits were used (four in each group) for the analysis of the biodistributions and bone uptakes of these radiopharmaceuticals to assess their potential for clinical applicability. Four hours after intravenous injection of approximately 37 MBq (1 mCi) Re-188-labeled diphosphonate preparations, whole body scans were performed using a large-field gamma camera equipped with a high resolution collimator. Bone-to-soft tissue ratios (B/S ratio) were calculated using a computer program. Our data showed that Re-188 HEDP with carrier (10(-4) M carrier) could accumulate in the skeletal system whereas very little absorption by bone was observed in the rabbits that were injected with carrier-free Re-188 HEDP. In addition, no significant bone uptake was demonstrated for Re-188 MDP or Re-188 HDP, with or without carrier. The B/S ratio was 25.06 in the Re-188 HEDP with carrier group but less than 3 in the other groups. In conclusion, HEDP is the best choice among these three bone-seeking drugs when labeled with Re-188. But, it is necessary to add carrier when preparing Re-188 HEDP for the treatment of bone metastases.

Animals↗

PubMed1981

The effects of 1-hydroxyethane-1,1-diphosphonate and dichloromethanediphosphonate on collagen synthesis by rabbit articular chondrocytes and rat bone cells.

Investigations were performed to assess the effects of dichloromethanediphosphonate on the synthesis of collagen by (1) isolated rabbit articular chondrocytes, (2) isolated rat calvaria bone cells and (3) bone explants from rats treated with the diphosphonates. The studies showed that dichloromethanediphosphonate, but not 1-hydroxyethane-1,1-diphosphonate, causes articular chondrocytes to increase net collagen biosynthesis, both when measured as 3H-labelled or as non-radioactive material, in a dose-related fashion. The increment in collagen synthesis was still evident with cells that were exposed continuously to the diphosphonate in primary as well as secondary culture; however, it declined with cells in tertiary culture and was absent after the fourth subculture. The type of collagen was not affected by the diphosphonate. The synthesis of collagen by bone cells was likewise increased with dichloromethanediphosphonate. No effects were detected with 1-hydroxyethane-1,1-diphosphonate was tested. Finally, when calvaria and tibiae from diphosphonate-treated rats were cultured in vitro, the positive effect of dichloromethanediphosphonate on collagen synthesis was also evident. 1-Hydroxyethane-1,1-diphosphonate, on the other hand, decreased the incorporation of [3H]proline into the collagen of calvaria and osseous tibial shafts and showed no effect on the collagen synthesis of the cartilaginous tibial heads.

Animals↗

PubMed1988

Diphosphonates and phosphate homoeostasis in man.

1. The effects of three intravenous diphosphonates (etidronate, clodronate and aminohexane diphosphonate) on phosphate homoeostasis were studied in 30 patients with Paget's disease of bone and in three patients with hypoparathyroidism. 2. In Paget's disease, all three diphosphonates induced significant increases in serum phosphate and renal tubular reabsorption of phosphate. This effect was most marked and persistent after etidronate, whereas in the clodronate- and aminohexane diphosphonate-treated patients the increases were less, of shorter duration and followed thereafter by significant decreases in serum phosphate and renal tubular reabsorption of phosphate. Unlike etidronate, both clodronate and aminohexane diphosphonate caused a significant reduction in serum and urinary calcium, with appropriate homoeostatic increases in immunoassayable parathyroid hormone. 3. Phosphaturic responses to infused parathyroid hormone were observed in two patients with etidronate-induced hyperphosphataemia. 4. In three hypoparathyroid patients, clodronate induced a more marked increase in serum phosphate and renal tubular reabsorption of phosphate than in Paget's disease, which was of comparable degree but of shorter duration than that after etidronate in Paget's disease. 5. These findings suggest that all three diphosphonates increase renal tubular reabsorption of phosphate, but that this effect is attenuated with those diphosphonates which induce secondary hyperparathyroidism.

Diphosphonates↗

PubMedDate not supplied

[Perspectives on therapy with diphosphonates in non-malignant diseases].

Diphosphonates inhibit bone resorption. This therapeutic effect found early recognition in the treatment of Paget's disease. The favorable long-term effect of the substance gives rise to a shorter therapy period. Due to increased fracture incidence as a result of osteoidosis observed under ethane-hydroxy diphosphomate (EHDP) administration, today amino-hydroxy-propylidine diphosphonate (APD) and dichloromethylene diphosphonate (clodronate) are preferred in the treatment of Paget's disease. Diphosphonates inhibit both osteoblasts and osteoclasts, thus being also used in the treatment of primary osteoporosis. Their efficacy in high-turnover osteoporosis in the form of monotherapy or within the framework of cyclical therapy schemes has been demonstrated by an increase in bone mass. Diphosphonates have played an important role in the therapy of steroid-induced osteoporosis. Prevention of osteopenic changes is of utmost significance: a prophylactic effect was demonstrated in immobilization osteoporosis. In prophylaxis, diphosphonates might also be applied in women after ovariectomy who had to undergo surgery before the menopause due to oncologic indications and in whom the administration of estrogens to prevent expected osteoporosis is contra-indicated. The favorable effect of diphosphonates on bone changes in Gaucher's disease implies an inhibition of macrophage-mediated bone resorption. The importance of this substance in orthopedics will further contribute to prevent ectopic ossification in hip endoprosthetics.

Aged↗

PubMedDate not supplied

[Effect of diphosphonic acids on alkaline phosphatase activity].

Kinetics was studied for the alkaline phosphatase activity inhibition by diphosphonic acids. When the ratio of Mg2+ and substrate (S) concentrations [( Mg2+]/[S]) is equal to 10, the process constants for methylene diphosphonic, amino methylene diphosphonic and hydroxyethylidene diphosphonic acids are 0.14, 0.12 and 0.35 mM, respectively. The inhibition is of competitive character. An increase in the Mg2+ concentration to the [Mg2+]/[S] = 40 ratio lowers the inhibition degree for all three diphosphonates; it follows a mixed mechanism. Thus, the inhibition of the alkaline phosphatase activity by diphosphonic acids is due to both competition of the inhibitor for the enzyme active centre and a decrease in the Mg2+ concentration, the phosphatase activator, because of Mg2+ complexing with diphosphonates.

Alkaline Phosphatase↗

PubMed1976

Effect of diphosphonates on adenosine 3':5'-cyclic monophosphate in mouse calvaria after stimulation by parathyroid hormone in vitro.

1. The diphosphonates, disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethylene diphosphonate (Cl2MDP), inhibit bone resorption in animals and in explanted bone in tissue culture. The possibility that these effects might be due to inhibition of skeletal adenylate cyclase has been studied. 2. EHDP and Cl2MDP, added for 30 min to the incubation medium at concentrations known to inhibit bone resorption, had no effect on basal content of adenosine 3':5'-cyclic monophosphate (cyclic AMP) of mouse calvaria incubated in vitro, nor did they inhibit the rise in cyclic AMP induced by bovine parathyroid hormone. 3. Pretreatment of mice for 3 days with Cl2MDP also had no effect on cyclic AMP under basal conditions or after incubation of explanted calvaria with parathyroid hormone in vitro. EHDP under similar conditions slightly inhibited the increase induced by parathyroid hormone but had no effect on basal concentrations of cyclic AMP. 4. It is suggested that the inhibition of adenylate cyclase is not an essential feature of the reduction of bone resorption by diphosphonates, which may act by direct inhibitory effects on the dissolution of hydroxyapatite and perhaps by other unidentified effects on bone cells. Key words: adenosine 3':5'-cyclic monophosphate, bone, dichloromethylene diphosphonate, diphosphonates, ethane-1-hydroxy-1,1-diphosphonate, parathyroid hormone.

Animals↗

PubMed1975

Distribution of 99mTc-Sn diphosphonate and free 99mTc-pertechnetate in selected soft and hard tissues.

Because increased uptake of 99mTc-diphosphonate (ethane-hydroxy-1, 1-diphosphonate) occasionally occurs in the anterior neck region, the possible increased affinity of the diphosphonate bone-scanning agent for cartilage was investigated. In vivo scintigraphic studies and organ analyses from rats and rabbits injected with this bone scintigraphic agent were performed. Trachea-to-muscle uptake ratios were a high 45:1 in adult Sprague-Dawley rats and approached the femur-to-muscle ratio of 93:1. Technetium-99m-diphosphonate uptake was also increased, but to a lesser extent, in xiphoid cartilage, tendon, and ear cartilage; this was proportional to the calcium content of the organ. The thyroid showed a high affinity for free pertechnetate but not 99mTc-diphosphonate, providing further evidence that the increased neck uptake of this 99mTc-diphosphonate is due to tracheal, not thyroid activity. In addition, premedication of three patients with 200 mg of potassium-perchlorate did not block this neck uptake. Interpretation of scintigraphs performed with 99mTc-diphosphonate that show lesions in the cervical spine should take into account the potential for false-positive readings caused by this increased tracheal uptake.

Achilles Tendon↗

PubMedDate not supplied

Effects of diphosphonates on glycosaminoglycan synthesis and proteoglycan aggregation in normal adult articular cartilage.

The effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethylene diphosphonate (Cl2MDP) on glycosaminoglycan synthesis and macromolecular organization of proteoglycans have been examined in normal adult canine cartilage. One to 500 micron of either compound produced reversible inhibition of glycosaminoglycan synthesis to about 70% of control levels, whereas lower concentrations had no effect. Based on Sephadex G-200 chromatography, the average hydrodynamic size of glycosaminoglycans in diphosphonate-treated cartilage was similar to that of those in control cartilage. In most cases proteoglycan aggregates from diphosphonate-treated cartilage were smaller in hydrodynamic size than those from control cartilage, as judged by Sepharose 2B elution profiles. The size of purified proteoglycan subunits, obtained after dissociation of the aggregates with 4 M guanidinium chloride or after incubation of the aggregates with hyaluronic acid beta1 leads to 3 hydrolase, was not affected by the diphosphonates. Furthermore, proteoglycans from diphosphonate-treated cartilage did not interact in vitro with hyaluronic acid, suggesting that diminished proteoglycan aggregation may have resulted from an abnormality in the hyaluronate-binding region of the proteoglycan core protein.

Animals↗

PubMed1979

Effect of diphosphonates on hydroxyapatite formation induced by calcium-phospholipid-phosphate complexes.

The diphosphonates disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and disodium dichloromethylene diphosphonate (Cl2MDP) prevent hydroxyapatite (HA) formation in metastable calcium phosphate solutions, induced by calcium-phospholipid-phosphate complexes and by the acidic phospholipids phosphatidyl serine and phosphatidyl inositol. The diphosphonates appear to act not only as HA crystal poisons but also as surfactants which probably change the nature of the lipid micelle and the charge and conformational properties of the lipid molecules. The surfactants sodium dodecyl sulfate (SDS) and Non-Idet P-40 (NP-40), like the diphosphonates, prevent HA formation by the acidic phospholipids and complexed lipids, but do not act as HA surface poisons. The lipid surfactant lyso-phosphatidyl serine did not induce HA formation from solution. The relevance of the ability of the diphosphonates to act as lipid surfactants to the in vivo use of these agents is discussed.

Calcium↗

PubMed1979

Effects of 1-hydroxyethane-1,1-diphosphonate and dichloromethanediphosphonate on rabbit articular chondrocytes in culture.

Investigations were carried out to assess the effects of disodium 1-hydroxyethane-1,1-diphosphonate and disodium dichloromethanediphosphonate (compounds containing a P-C-P bond) on isolated rabbit articular chondrocytes in culture. Studies on growth behaviour showed that both diphosphonates displayed inhibitory actions, dichloromethanediphosphonate producing the larger effect. Both compounds inhibited the uptake of 2-deoxy-d-glucose, dichloromethanediphosphonate once more being the more potent of the two. The uptake of alpha-aminoisobutyrate was considerably increased by chondrocytes treated with dichloromethanediphosphonate, whereas 1-hydroxyethane-1,1-diphosphonate showed no effects. The biosynthesis of sulphated extracellular macromolecules secreted by the cells into the pericellular space as well as into the growth medium was greatly increased by dichloromethanediphosphonate but not by 1-hydroxyethane-1,1-diphosphonate. The stimulatory effect was dose-dependent. Short-term exposure of already confluent cells to dichloromethanediphosphonate as opposed to growing the cells to confluence in the presence of the diphosphonate revealed that the stimulatory effects were already evident after 24h, indicating that cell division is not necessarily required to produce the observed effects. The increment in proteoglycan synthesis was still evident with cells that were exposed continuously to the diphosphonate in primary as well as secondary culture. Pulse-chase experiments together with studies on the enzyme arylsulphatase revealed that the appearance of increased amounts of proteoglycans was the result of a stimulation in synthesis and not due to an inhibition in turnover.

Aminoisobutyric Acids↗

PubMed1978

Uptake by bone of pyrophosphate, diphosphonates and their technetium derivatives.

1. The uptake of inorganic pyrophosphate (PPi) from blood to bone was investigated in the rat in vivo. 2. PPi is taken up by the bone, where it appears both as PPi and as inorganic orthophosphate (Pi). The latter is due at least partly to local hydrolysis. 3. The fraction of injected PPi taken up by bone, measured as total PPi, was in the same range as that of technetium-tin-PPi, diphosphonates, technetium-tin-ethane-1-hydroxy-1,1-diphosphonate and Pi, but lower than that of calcium. 4. The plasma half-life of PPi is in the same order of magnitude as that of technetium-tin-PPi, diphosphonates, technetium-tin-ethane-1-hydroxy-1,1-diphosphonate, Pi and calcium. 5. PPi, diphosphonates and their technetium complexes are only partly ultrafiltrable in plasma. 6. It appears that the technetium complexes behave in a similar fashion to free PPi or diphosphonate.

Animals↗

PubMed2004

Effects of ethane-1-hydroxy-1,1-diphosphonate on ossification of the posterior longitudinal ligament in Zucker fatty rats.

PURPOSE: Using Zucker fatty rats as an animal model, we evaluate the effectiveness of ethane-1-hydroxy-1,1-diphosphonate on ossification of the posterior longitudinal ligament by histopathologically investigating the prodromal, early, and advanced stages of ossification of the spinal ligaments. METHODS: 73 Zucker fatty rats were allocated to the ethane-1-hydroxy-1,1-diphosphonate group (n=33) and the control group (n=40). The former group was fed ethane-1-hydroxy-1,1-diphosphonate daily. The feed was given starting 2 months after birth and continued until the rats were killed at 3 to 18 months later. Chemical analysis of the blood, radiographic tests, and histopathological examination were then conducted for both groups. RESULTS: The results showed that ossification of the spinal ligaments involved excessive cartilage cell proliferation around areas affected by enthesitis; enlargement of the fibrocartilage tissue layer; ligament thickening; calcification of the matrix around the cartilage cells; and ossification of the spinal ligaments through enchondral ossification. Radiographic examinations showed that osteoproliferation in vertebral bodies in rats receiving ethane-1-hydroxy-1,1-diphosphonate was generally suppressed compared with controls, whereas histopathological examinations found no clear difference in cartilage cell proliferation in areas affected by enthesitis between the two groups, indicating the absence of calcification or osteo-proliferation in areas affected by enthesitis for the rats receiving ethane-1-hydroxy-1,1-diphosphonate. CONCLUSION: Ethane-1-hydroxy-1,1-diphosphonate is effective in suppressing progressive ligament ossification.

Animals↗

PubMed1987

Prevention of heterotopic bone formation: clinical experience with diphosphonates.

Heterotopic bone formation after total hip arthroplasty is a common occurrence in patients with osteoarthritis, and severe amounts of ectopic bone may limit motion or cause pain. Diphosphonates have been suggested as a method of preventing ectopic bone formation, but no long-term clinical evaluation of their effectiveness has been published. Because patients with osteoarthritis appeared to respond well to diphosphonate therapy in an earlier study, we thought that they would be an appropriate group of patients to study. We evaluated the results of 177 patients with 200 total hip arthroplasties performed for primary osteoarthritis. Considerable postoperative heterotopic bone formation (classes III and IV according to the classification system of Brooker and associates) was found in 36 hips (18%). The incidence of heterotopic bone formation was found to be as high as in the patients who had received either a placebo or no drug therapy. The postoperative range of motion of the hips, as well as ratings for pain, walking, and function, did not differ significantly between the treated and untreated groups. Diphosphonates (EHDP) have been demonstrated to inhibit the growth of hydroxyapatite crystals in vitro by chemisorption onto the crystal surface and thus have been thought to have the potential of preventing pathological calcification in vivo. However, diphosphonates have no inhibitory effect on the formation of osteoid matrix, and the delay in mineralization of matrix is reversed when therapy is discontinued. Although this delay in mineralization was known at the onset of these clinical trials, we hoped that the ultimate amount of heterotopic bone would be less in the treated patients and that the range of motion would be improved as a result of delaying the process of mineralization. Unfortunately, the final range of motion in the diphosphonate-treated patients did not differ significantly from that in the untreated group, and the final amount of heterotopic ossification was not reduced. Therefore diphosphonate therapy must be considered ineffective.

Clinical Trials as Topic↗

PubMed1983

Comparative quality control of 99mTc-Pyrophosphate and 99mTc-diphosphonate radiopharmaceuticals.

The results of analysis of 99mTc-Pyrophosphate (99mPyP), taken as a representative of the group of compounds having an organic P-O-P bond, and of the three diphosphonate compounds: methylene diphosphonate (MDP), 2,3-dicarboxy propane diphosphonate (DPD) and ethane-1-hydroxy-1, 1-diphosphonate (EHDP), which differ in their chemical structure, are shown. Also, some physicochemical parameters such as chloroform-water apparent partition coefficient, the osmotic pressure and pH values in final preparations were studied. The radiochemical purity of these radiopharmaceuticals was determined by the two methods: Sephadex chromatography for separation of 99mTc-hydrolysate and TLC on silica gel with 85% methanol for the determination of free 99mTcO-4. The yield of labelling for both methods was over 90%. Also, pharmacokinetic parameters such as binding to the plasma proteins and to erythrocytes were determined. 99mTc-PyP binding to plasma proteins was higher than the binding of diphosphonate compounds. The quantitative distribution of preparations was determined in experimental animals.

Animals↗

PubMed1987

Studies on diphosphonate kinetics. Part II: Whole body bone uptake rate during constant infusion--a refined index of bone metabolism.

To elaborate the understanding of diphosphonate kinetics, a non compartmental analysis is introduced. Using continuous infusion of 99mTc-methylene diphosphonate (Tc-MDP) and 51Cr-EDTA, as a cotracer, the diphosphonate clearance to bone (BDC) can be calculated. BDC is found to correlate well with the 24 h whole body retention of diphosphonate (WBR) (r = 0.89, P less than 0.01) when renal function is normal, but not in cases of reduced 51Cr-EDTA clearance. These findings indicate that BDC measurements are superior to the WBR technique in the estimation of bone turnover, especially when renal function is reduced. The BDC measurements may also constitute a useful tool for studies of diphosphonate uptake in bone, the foundation of bone scintigraphy.

Bone and Bones↗

PubMed1983

Effects of dichloromethylene diphosphonate in women with breast carcinoma metastatic to the skeleton.

Ten women with skeletal metastases from breast carcinoma received dichloromethylene diphosphonate (Cl2MDP), an inhibitor of osteoclast function, in a placebo-controlled, double-blind, crossover study. Eight of these patients had either hypercalcemia or hypercalciuria, and all 10 had elevated urinary hydroxyproline levels as evidence of active skeletal disease. Eight patients had moderate to severe bone pain. After eight weeks of oral dichloromethylene diphosphonate treatment (3,200 mg per day), either preceded by or followed by an eight-week placebo period, seven of eight patients with hypercalciuria had significant reductions in urinary calcium levels, and nine of 10 had reductions in urinary hydroxyproline levels (significant in eight) when the dichloromethylene diphosphonate treatment periods were compared with prestudy or placebo periods. Additionally, seven of eight subjects had decreased pain with dichloromethylene diphosphonate. There were no adverse effects other than transient diarrhea in some patients. We conclude that oral dichloromethylene diphosphonate can significantly inhibit osteoclast-mediated bone destruction in patients with bone metastases from breast cancer.

Administration, Oral↗

PubMed1987

Beneficial effects of aminohexane diphosphonate in patients with Paget's disease of bone resistant to sodium etidronate.

Clinical and biochemical resistance to sodium etidronate therapy is not rare in patients with severe Paget's disease of bone, especially after several courses of treatment. Sixteen patients with Paget's disease of bone and well-documented resistance to sodium etidronate were treated with a new diphosphonate, aminohexane diphosphonate, given orally for three months at a daily dose of 400 mg. These patients comprised a selected population of patients with very active disease, as shown by a mean 20-fold increase of serum alkaline phosphatase levels before aminohexane diphosphonate therapy. Aminohexane diphosphonate induced a striking reduction of serum alkaline phosphatase and urinary hydroxyproline levels sustained for up to 18 months after withdrawal of treatment. Two patients had a relapse 14 to 16 months after treatment, and received a second course of aminohexane diphosphonate with the same efficacy. This was accompanied by marked clinical improvement, a reduction of the radioisotope uptake by pagetic bones, and radiologic healing of osteolytic lesions in some cases. Iliac crest biopsy specimens taken after tetracycline double-labeling showed no impairment of bone mineralization. No clinical or biochemical adverse effects have been observed.

Aged↗