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Results for “Diphosphonates”

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PubMed1983

Diphosphonate treatment for heterotopic ossification in spinal cord injury patients.

Nine patients who had spinal cord injury and were receiving diphosphonate therapy for established neurogenic heterotopic ossification in 14 hips were followed up for an average of 14 months. Diphosphonate therapy at a dosage of 10 mg/kg/day when prescribed an average of 26 days after diagnosis did not prevent radiographically evident progression of heterotopic ossification. The interval of one to 30 days between clinical diagnosis and institution of diphosphonate treatment did not appear to affect the duration of radiographic progression or the final radiographic grade at maturity. Disodium etidronate therapy did not prevent the appearance of heterotopic ossification in three previously unaffected hips, although the final radiographic grade was mild. The radiographic progression of heterotopic ossification averaged 5.3 months. No clinically detectable side effects were attributable to the medication at the dosage prescribed after an average of 14 months of therapy. Due to the radiographic progression noted in patients who received 10 mg/kg/day, diphosphonate has been increased to dosages of 20 mg/kg for six months after early diagnosis.

Adolescent↗

PubMed1975

Enzymatic inhibition of diphosphonate: a proposed mechanism of tissue uptake.

Enzymes have been proposed as tissue receptors that bine 99mTc-stannous diphosphonate and its analogs. Incubation of diphosphonate with several enzymes demonstrated inhibition of acid and alkaline phosphatase activity but showed no effect on glutamic oxalacetic transaminase and lactate dehydrogenase activity. Complete reversal of the diphosphonate-induced inhibition of alkaline phosphatase activity occurred when calcium ion was added to the reaction. The specificity of calcium to induce reversal was dispelled when magnesium ion gave identical results. Diphosphonate-induced inhibition of acid phosphatase, however, was not reversed by calcium or magnesium.

Acid Phosphatase↗

PubMed1981

Parenteral diphosphonates for treating malignant hypercalcemia.

Two diphosphonates, EHDP (disodium etidronate, or ethanehydroxy-diphosphonate) and Cl2MDP (disodium clodronate, or dichloromethylene-diphosphonate) were injected in various doses in six patients with one or multiple episodes of malignant hypercalcemia. All patients responded well to the drugs after a delay period of two to seven days. The tolerance of the drugs was excellent. EHDP, and especially Cl2MDP, are promising agents for treating hypercalcemia and inhibiting bone resorption in malignant disorders.

Aged↗

PubMed1980

Biochemical and clinical responses to dichloromethylene diphosphonate (Cl2MDP) in Paget's disease of bone.

Dichloromethylene diphosphonate (Cl2MDP, or clodronate disodium) is one of the most potent of the known diphosphonates as an inhibitor of bone resorption and differs from EHDP in that it does not inhibit skeletal mineralization. It is one of the second generation diphosphonates now undergoing clinical evaluation. In the study described here Cl2MDP was given by mouth (800-1600 mg/day for 6 months) to 35 patients with symptomatic Paget's disease of bone. Cl2MDP induced a marked fall in serum alkaline phosphatase and urinary hydroxyproline to normal or near normal values in all patients. This was accompanied by clinical improvement in all but 4 patients. Cl2MDP appears to be another effective oral drug for the treatment of Paget's disease of bone and compares favorably with the calcitonins and EHDP.

Alkaline Phosphatase↗

PubMed1980

The effect of prostaglandin synthesis inhibitors and diphosphonates on tumour-mediated osteolysis.

Previous studies have shown that the prostaglandin synthesis inhibitor indomethacin reduced osteolysis produced by the experimental VX2 carcinoma, probably by inhibiting the stimulation of osteoclasts by prostaglandin E2. This study was carried out to determine whether prostaglandin inhibitors affect the tumour osteolysis produced by human mammary carcinoma as well as the VX2 carcinoma. The effect of diphosphonates on reducing tumour osteolysis was also investigated, since diphosphonates directly affect bone resorption. The results indicated that various non-steroidal, anti-inflammatory agents which inhibit prostaglandin synthesis reduced the osteolysis produced by human mammary or rabbit VX2 carcinomas. The diphosphonate compounds also produced a significant inhibition of tumour osteolysis. The results confirm the findings of Powles and his colleagues (1) that aspirin (also a prostaglandin synthesis inhibitor) reduced the osteolysis induced by human mammary carcinoma. It is suggested that these agents be evaluated as adjuvant therapy in patients with apparently 'early' mammary cancer in a controlled clinical trial.

Animals↗

PubMed1984

Blood flow and bone uptake of 99mTc-labeled methylene diphosphonate.

In mature dogs with comparable levels of bone remodeling, we produced either increased (with adenosine triphosphate) or decreased (with epinephrine) blood flow to one hindlimb. In 13 dogs (five control, four with increased flow, and four with decreased flow), we compared uptake, at 3 h after injection of radiolabeled diphosphonate in the mid-tibia, with blood flow as determined by microspheres. Blood flow was determined with 85Sr-labeled microspheres, and determination of uptake of 99mTc methylene diphosphonate (99mTc-MDP) was by a gamma detector. There was a linear relationship between changes in diphosphonate uptake and changes in blood flow at decreased and normal flows; however, at high flows the relationship was nonproportional, indicating a disproportionately slower increase in 99mTc-MDP uptake with increasing blood flow. In six dogs an initial 1-h uptake curve of 99mTc-MDP was determined in both control and experimental limbs under states of increased and decreased blood flow. The 30-min uptake value, 60-min uptake value, area under the curve, and the slope of the curve were related to flow as determined by microspheres. The data are consistent with the hypothesis that deposition of bone-concentrating isotopes such as 99mTc-MDP is partly controlled by blood flow; at supranormal and normal flows tracer uptake is closely related to blood flow, but at supranormal flow rates it is not and appears to be diffusion limited.

Adenosine Triphosphate↗

PubMed1984

Cutaneous calciphylactic reactions in the mouse and the rat and the effects of diphosphonates on the reaction in the rat.

Calciphylaxis is a local tissue calcific reaction at the site of an injection of challenger substance given a critical time period after the oral administration of a sensitizer substance such as dihydrotachysterol (DHT), vitamin D or parathormone. Cutaneous calciphylaxis is readily induced in the rat but not in the mouse and this may be because, in the latter, the challenger substance is absorbed rapidly by macrophages. In the rat the administration of 500 micrograms/0.1 ml of DHT followed after 24 h by the subcutaneous (SC) injection of ferric chloride (FeCl3) (30 micrograms/0.1 ml) is followed rapidly by calcification of the SC site. There is an early transient acute inflammatory reaction with the incrustation of collagen fibres by the iron salt and an apparent exudation of calcium and phosphate ions from the bloodstream. These ions also become associated with collagen fibres. Two days after injection macrophages and multinucleated giant cells become the dominant cells. Calciphylaxis is a useful experimental model of ectopic calcification and is associated with an initial hypercalcaemia. The diphosphonates ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP) are effective inhibitors of the calciphylactic reaction when administered prior to the initiation of the experimental procedure.

Animals↗

PubMed1980

Skeletal uptake of diphosphonate: a review.

The diphosphonates are currently the skeletal imaging agents of choice and while extremely sensitive for bony abnormality their mechanism of action remains poorly understood. The current concepts in bone uptake mechanisms are reviewed and it is concluded that diphosphonate uptake is most likely related to sites of newly forming bone with diphosphonate adsorbed onto the surface of hydroxyapatite crystals. In situations where there is markedly increased skeletal uptake of tracer, increased vascularity alone cannot account for changes in tracer uptake and changes in skeletal extraction, related to newly forming bone are more important.

Alkaline Phosphatase↗

PubMed1987

Studies on diphosphonate kinetics. Part I: Evaluation of plasma elimination curves during 24 h.

To improve the understanding of diphosphonate affinity to metabolically active bone, the underlying diphosphonate kinetics have been evaluated and compared to Cr-EDTA kinetics. MDP binds to plasma proteins, varying from 25% initially to approximately 70% after 24 h. The renal clearance of diphosphonate is found to be equal to Cr-EDTA clearance. Using simultaneous bolus injection of 99Tc-MDP and 51Cr-EDTA, it has been possible to obtain a coarse estimate of bone uptake of MDP. This uptake is found to correlate well with s-alkaline phosphatase, but since MDP binding to bone is reversible, the plasma elimination curve is not monoexponential. Therefore it has not been possible to describe the uptake of MDP in bone mathematically.

Bone and Bones↗

PubMed1977

The effect of pyrophosphate and diphosphonates on calcium transport in red cells.

The effect of 0.5 mM pyrophosphate (PPi), disodium ethane-4-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethane diphosphonate (Cl2MDP) on the ATP-dependent Ca2+ extrusion from the human red cell ghosts was studied. PPi and Cl2MDP had no effect, when introduced into the cells or added outside to the medium. EHDP slightly increased the calcium concentration in the released cells and slightly decreased the rate constant of the calcium transport, having opposite effects when it was inside or outside the cells. PPi and the 2 diphosphonates were not found to move easily across the red cell membrane.

Biological Transport, Active↗

PubMed1981

Effects of two diphosphonates (EHDP and Cl2MDP) on serum uric acid in pagetic patients.

The effects on serum uric acid (SUA) of two diphosphonates (EHDP at 5 and 20 mg/kg/day and Cl2MDP at 400 and 1600 mg/day) were studied in 49 pagetic patients treated for 6 months. Patients were divided into two groups: group I, initially normouricemic (SUA less than 385 mumol/l); group II, initially hyperuricemic (SUA greater than or equal to 385 mumol/l). SUA was significantly decreased (P less than 0.01) after 6 months of diphosphonate therapy in all group II patients. However, 3 months after withdrawal of therapy, SUA returned to values not significantly different from those initially recorded in this group. SUA did not change during or after treatment in the group I patients. Groups I and II could not be differentiated on the basis of initial serum alkaline phosphatase or urinary hydroxyproline values. In response to therapy, both groups showed the same reduction in these parameters. These results suggest that diphosphonates have no effect at a single level in uric acid metabolism. They certainly reduce the part of the urate pool coming from the nucleic acids of the increased bone cell population by reducing the number of osteoclasts and osteoblasts, which is extremely high in pagetic bone. They also must act on uric acid metabolism through other mechanisms which need to be investigated in further studies.

Adult↗

PubMed1988

Diphosphonates are potent inhibitors of mammalian inorganic pyrophosphatase.

Methanediphosphonate and 12 analogs thereof with different substituents at the carbon atom are potent competitive inhibitors of highly purified rat liver and bovine heart inorganic pyrophosphatases. The inhibition constants for the most effective diphosphonates, which contain an NH2 or OH group at the bridge carbon atom, are in the micromolar range. Yeast and Escherichia coli pyrophosphatases are markedly less sensitive to the diphosphonates. Pyrophosphatase inhibition may be related to the numerous biological effects exerted by diphosphonates.

Animals↗

PubMed1978

The inhibitory effect of new diphosphonic acids on aortic and kidney calcification in vivo.

Three new diphosphonic acids, i.e. compounds containing a P-C-P bond, have been investigated for their ability to inhibit the vitamin D-induced calcification of aortas and kidneys in rats. The compounds were applied orally in various doses. All of the compounds, which had previously been shown to effectively inhibit the in vitro crystallization of apatite, markedly decreased the amount of calcium deposited in aortas and kidneys. One of the new compounds was substantially more effective than ethane-1-hydroxy-1,1-diphosphonic acid (EHDP), which was used as a reference compound. Diphosphonic acids might be used therapeutically in man against soft tissue calcification.

Animals↗

PubMed1989

Short-term effects on bone and mineral metabolism of 4-amino-1-hydroxybutylidene-1,1-diphosphonate (ABDP) in Paget's disease of bone.

To study the short-term effects on mineral and bone metabolism of a recently introduced amino-diphosphonate (4-amino-1-hydroxybutylidene-1,1-diphosphonate or ABDP), 10 patients suffering from active Paget's disease were examined. Each subject received intravenously 5 mg/day of ABDP for 4 days and the effects of treatment were monitored for 12 days. ABDP administration was followed by an early and significant decrease of the urinary hydroxyproline and calcium excretion, of the theoretical renal threshold for phosphate of the serum calcium. Serum phosphate also decreased, while its urinary excretion increased. Intact parathyroid hormone levels at the end of treatment were four times higher than basal levels. Total and bone alkaline phosphatase tended to decrease only slightly at the end of the observation, whereas serum osteocalcin, tended to increase. These findings indicate that the earlier effect of ABDP is a profound inhibition of bone resorption, which brings about a compensatory parathyroid hormone response. The decrease of urinary hydroxyproline follows an exponential curve, with a calculated half-life of 2.2 days, suggesting an approximate equivalency of 5 mg/day ABDP to slightly more than 30 mg/day 3-amino-1-hydroxypropylidene-1,1-diphosphonate. Bone formation seems scarcely influenced in the short-term, but osteoblastic indices show a contrasting behaviour, which may reflect a different biological origin and/or significance.

Adult↗

PubMed1981

Diphosphonates: history and mechanisms of action.

The history of diphosphonates began with studies of inorganic pyrophosphate. This compound was found to occur in many biological fluids and inhibited the precipitation of calcium phosphates. It also slowed the transformation of amorphous calcium phosphate to its crystalline form, and inhibited crystal aggregation and dissolution. These observations suggested that it might be a compound of physiological or pathophysiological significance, perhaps in hypophosphatasia and in renal lithiasis. Diphosphonates are compounds where the P-O-P bond of pyrophosphate is replaced by a P-C-P bond. Many diphosphonates have been synthesized and tested and some relationship of their structure to the spectrum of biological effects has been observed. These analogues have similar properties to pyrophosphate, but unlike pyrophosphate they are resistant to enzymic degradation. Their experimental properties have led to their clinical development as bone scanning agents and in the treatment of disorders of ectopic mineralization and increased bone resorption.

Animals↗

PubMed1985

Effect of pyrophosphate and two diphosphonates on 45Ca and 32Pi uptake and mineralization by matrix vesicle-enriched fractions and by hydroxyapatite.

Inorganic pyrophosphate (PPi) and two diphosphonates, ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP), were found to inhibit in vitro mineralization induced by matrix vesicle-enriched fractions from chicken epiphyseal cartilage. Inhibitor concentrations from 0.20 to 20 microM caused a dosage-dependent decrease in 45Ca and 32Pi uptake by the vesicle fraction. These inhibitors were also tested in a hydroxyapatite (HA)-seeded system to help distinguish between effects on the mineral vs nonmineral portions of the vesicle fraction. The order of inhibition of the HA-seeded system was EHDP greater than PPi greater than Cl2MDP, except for inhibitor concentrations of 0.20 microM where EHDP was the least inhibitory. This variation may be due to differences in the binding of the inhibitors to HA crystals. In general, inhibition of HA mineralization was greatest during later time periods, whereas vesicle ion uptake was affected more during early stages of incubation. The differential effects of the three inhibitors were most obvious at the 2.0 microM concentration. With PPi substantial inhibition of HA-seeded mineralization was observed even in late stages of the study; in contrast, with time the vesicle fraction overcame this inhibition. This suggests that alkaline phosphatase, an enzyme notably enriched in matrix vesicles, catalyzed the hydrolysis of PPi, reducing its concentration to a level where mineralization could proceed. Our findings show that matrix vesicle-induced mineralization differs significantly from apatite-induced mineralization. The data support the concept that vesicle alkaline phosphatase acts, at least in part, to remove physiological crystal growth inhibitors.

Alkaline Phosphatase↗

PubMed1977

[Sources of error in the interpretation of bone scans with 99mTc-diphosphonate (author's transl)].

Errors in the interpretation of bone scans with 99mTc-diphosphonate may be due to summation of radio-activity from superimposition of various bone structures. Lesions with increased bone turn-over as well as reactive hyperaemia result in increased uptake. The possibility of extraosseous uptake of diphosphonate must be borne in mind during the evaluation of bone scans. The kidneys and lower urinary tract must be considered. Absent or slight uptake by the kidneys with good demonstration of bone suggests increased diphosphonate uptake by the bones. Special attention should also be paid to zones of decreased uptake, since these are also due to abnormalities in the bone.

Bone Diseases↗

PubMed1979

Myocardial infarct imaging with 99mTc-pyrophosphate and 99mTc-methylene diphosphonate: lack of correlation.

A prospective study of eight patients with recent transmural myocardial infarction was performed using 99mTc-Sn-pyrophosphate and 99mTc-Sn-methylene diphosphonate in each patient. All pyrophosphate scans were strongly positive whereas the diphosphonate scan was strongly positive in only one case. We conclude that 99mTc-Sn-pyrophosphate is preferable to 99mTc-Sn-methylene diphosphonate for myocardial imaging.

Diphosphates↗