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Results for “Diphosphonates”

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PubMed1993

Decrease of serum calcium concentration and lost influence of calcium on parathyroid hormone release in a patient with primary hyperparathyroidism after treatment with diphosphonates.

Prolonged decrease of elevated serum calcium levels after treatment with diphosphonates in patients with primary hyperparathyroidism (pHPT) is very rare. A patient with water clear cell hyperplasia and five enlarged glands is presented who received diphosphonates (day 1 through day 8 dichloromethylene diphosphonate orally and a single dose of 60 mg pamidronate on day 8 intravenously) leading to a significant fall in serum calcium levels. Surprisingly, there was no reactive increase in intact parathyroid hormone (PTH) in the following 18 days. Patients with missing PTH regulation to hypocalcemia after diphosphonates who need a period of stabilization prior to parathyroid surgery might benefit most from this therapy.

Aged↗

PubMed1980

Effects of pyrophosphate and diphosphonates on the dissolution of hydroxyapatites using a flow system.

Pyrophosphate and diphosphonate ions have been said to diminish the dissolution of hydroxyapatite crystals, because they lower the equilibrium concentrations of calcium and phosphate ions in the bulk solution around hydroxyapatite crystals in a closed system. However, in a closed system these effects are not necessarily due to an effect on dissolution alone. In this paper we have used a continuous flow system to study the effects of pyrophosphate and two diphosphonates, ethane-1-hydroxy-1,1,-diphosphonate and dichloromethane diphosphonate, on the dissolution of hydroxyapatite. All three compounds decreased markedly the rate of dissolution of hydroxyapatite as well as the exchangeable pools of calcium and phosphate ions around the crystals.

Calcium↗

PubMed1982

Comparison of two parenteral diphosphonates in hypercalcemia of malignancy.

The two diphosphonates, ethane-hydroxy-diphosphonate (EHDP) and dichloromethylene-diphosphonate (Cl2MDP) were injected into 30 patients with one or multiple episodes of hypercalcemia caused by osteolytic metastases. All patients responded well to the treatment after a men delay of two days. Cl2MDP was slightly more efficient than EHDP, but there was no difference in serum calcium measured after five days of therapy with Cl2MDP or after 10 days of EHDP: in both cases, the calcium level was normal. No acute or long-term side effect has been observed. Parenteral diphosphonates may well be the treatment of first choice against malignant hypercalcemia.

Adult↗

PubMed1989

Diphosphonates inhibit human osteoblast secretion and proliferation.

In view of the beneficial effect of diphosphonates in Paget's disease and their suppressive effect on alkaline phosphatase, the action of three diphosphonates (aminohydroxypropylidene diphosphonate [APD], clodronate, and didronel) on cultured human osteoblasts in vitro was investigated. All three inhibited basal and 1,25(OH)2 cholecalciferol-stimulated alkaline phosphatase secretion and [3H]thymidine uptake by osteoblasts. It is concluded that diphosphonates consistently inhibit human osteoblasts through a direct action in addition to their known effect on inhibiting bone resorption and that these actions together may form the basis of their beneficial effect in vivo in patients with Paget's disease.

Alkaline Phosphatase↗

PubMed1995

Influence of disodium (1-hydroxythylidene) diphosphonate on bone ingrowth into porous, titanium fiber-mesh implants.

The influence of disodium (1-hydroxythylidene) diphosphonate on the bonding between bone and porous, titanium fiber-mesh implants was studied. Rectangular, porous, titanium fiber-mesh implant (15 x 10 x 2.4 mm) were implanted into the tibial bone of mature male rabbits. The rabbits were divided into six groups. Disodium diphosphonate was administered daily by subcutaneous injection to groups 1-5. Groups 1-4 received doses of 5.0, 2.5, 1.0, and 0.1 mg per kilogram of body weight per day for 8 weeks, respectively. Group 5 received a dose of 5 mg per kilogram of body weight per day for 4 weeks. Group 6 (control group) was given saline injections. At 8 weeks after implantation, the rabbits were killed. The tibiae containing the implants were dissected out and subjected to detachment tests. The failure load, when an implant became detached from the bone or when the bone itself broke, was measured. The interface of the bone and implant was investigated by Giemsa surface staining and contact microradiography. Giemsa surface staining and contact microradiography showed that porous implant bonding to bone tissue was inhibited by a high dose of disodium diphosphonate in groups 1, 2, and 5. Soft tissue was observed at the interface. In groups 3, 4, and 6, bone tissue ingrowth was observed at the interface between the porous implant and bone tissue. Growth of bone into the porous fiber-mesh implant of a cementless prosthesis is possible if a low dose of diphosphonate below 1.0 mg per kilogram of body weight is given subcutaneously.

Animals↗

PubMed1979

Increase in alkaline phosphatase activity in calvaria cells cultured with diphosphonates.

1. Dichloromethanediphosphonate and to a lesser degree 1-hydroxyethane-1,1-diphosphonate, two compounds characterized by a P-C-P bond, increased the alkaline phosphatase activity of cultured rat calvaria cells up to 30 times in a dose-dependent fashion. 2. Both diphosphonates also slightly inhibited the protein synthesis in these cells. 3. Thymidine, an inhibitor of cell division, did not inhibit the induction of the enzyme, indicating that the increase in enzyme activity was not due to the formation of a specific population of cells with high alkaline phosphatase activity. 4. The effect on alkaline phosphatase was suppressed by the addition of cycloheximide, an inhibitor of protein synthesis. 5. After subculturing the stimulated cells in medium without diphosphonates, the enzyme activity fell almost to the control value. 6. Bovine parathyrin diminished the enzyme activity of the control cells and the cells treated with dichloromethanediphosphonate; however, at high concentration the effect of parathyrin was greater on the diphosphonate-treated cells than on the control cells. 7. The electrophoretic behaviour, heat inactivation, inhibition by bromotetramisole or by phenylalanine, and the Km value of the induced enzyme were identical with that of the control enzyme.

Alkaline Phosphatase↗

PubMed1981

Increase in fatty acid oxidation in calvaria cells cultured with diphosphonates.

1. Cultured calvaria cells oxidized palmitate and octanoate to CO2 and water-soluble products. 2. When these cells were treated for 6 days with 0.025 and 0.25 mM-dichloromethanediphosphonate, oxidation of palmitate was increased, whereas that of octanoate was influenced less. 3. When the rate of oxidation was raised by increasing the palmitate concentration in the medium, the effect of the diphosphonate was decreased and finally disappeared. 4. 1-Hydroxyethane-1,1-diphosphonate had only minor effects. 5. The increase in palmitate oxidation appeared 2 days after the addition of dichloromethanediphosphonate, simultaneously with a fall in lactate production. (Inhibition of glycolysis by diphosphonates has already been shown.) 6. Cycloheximide, an inhibitor of protein synthesis, did not influence the effect of dichloromethanediphosphonate on the oxidation of palmitate and the production of lactate. 7. Cells cultured with dichloromethanediphosphonate showed a faster uptake of palmitic acid than did control cells. However, this observation did not explain the increased palmitate oxidation, since uptake was much faster than oxidation, and was therefore not the rate-limiting step. 8. 2-Bromopalmitate, an inhibitor of fatty acid oxidation, did not influence the inhibition of glycolysis by the diphosphonates. This inhibition, therefore, did not result from the increased oxidation of palmitate. It is also unlikely that the increased oxidation of palmitate is connected with the inhibition of glycolysis.

Animals↗

PubMed1987

Effect of single high dose infusions of aminohydroxypropylidene diphosphonate on hypercalcaemia caused by cancer.

Single intravenous infusions of 30 mg aminohydroxypropylidene diphosphonate were given to 16 patients who had malignant hypercalcaemia to assess host tolerance and the effect on serum calcium concentration. Ten of these patients also received intravenous rehydration or corticosteroids, or both. The serum calcium concentrations decreased significantly after treatment with aminohydroxypropylidene diphosphonate. Ten patients became normocalcaemic (normal range, adjusted for serum albumin, 2.25-2.75 mmol/l), two became hypocalcaemic, three showed decreases in serum calcium concentrations of more than 0.75 mmol/l, and one showed a decrease of more than 0.55 mmol/l. Only one patient had a minimum concentration greater than 2.77 mmol/l. Aminohydroxypropylidene diphosphonate was effective in metastatic and non-metastatic hypercalcaemia, and its hypocalcaemic effect was prolonged in some cases. There were no appreciable side effects. Single high dose infusions of aminohydroxypropylidene diphosphonate could replace conventional daily lower dose infusions, but the optimum frequency of high dose infusions remains to be determined.

Adult↗

PubMed1990

Improvement in the deformity of the face in Paget's disease treated with diphosphonates.

We studied nine patients with Paget's disease affecting the skull or facial bones, who were subsequently treated with either dichloromethylene diphosphonate (clodronate) or ethylene-1-hydroxy-1,1-diphosphonate (etidronate). Long-term treatment induced a clinical and biochemical improvement in eight, and this was associated with a reduction in maxillary or skull volume as assessed by quantitative stereophotogrammetry. The one patient whose disease was resistant to treatment with diphosphonate, showed no change in maxillary shape. These studies suggest that the long-term control of disease activity attained with diphosphonates, results in the improvement of skeletal deformity.

Aged↗

PubMed1990

Inhibition of ectopic calcification of glutaraldehyde crosslinked collagen and collagenous tissues by a covalently bound diphosphonate (APD).

Calcification of collagen-derived prosthesis, such as glutaraldehyde crosslinked porcine heart valves or heart valves assembled out of bovine pericardium, presents a major clinical problem. Their subcutaneous implantation into young rats provides us with a reproducible method of assessing this form of ectopic calcification. Long-term implantation is essential, since some materials which do not calcify within the first month frequently exhibit a delayed calcific response. Crosslinked pericardium is much more likely to calcify than crosslinked tendon or reconstituted crosslinked pepsin extracted bovine type I collagen. The covalent binding of a diphosphonate to collagen and collagen-rich tissues can prevent calcification. The binding of this diphosphonate and its ability to inhibit calcification can be enhanced by increasing the number of amino groups on the collagen molecule. The degree of calcification is inversely related to the number of diphosphonate molecules covalently bound to collagen. Under standard conditions, chemical modifications appear to occur primarily on the surface of the collagen fibrils, as evidenced by the relationship between the number of molecules of APD bound and fibril diameter. The bound diphosphonate seems to interfere with crystal growth and prevent the formation of highly insoluble hydroxyapatite on the surface and interstices of the collagen fibrils.

Animals↗

PubMed1986

Severe systemic reaction to diphosphonate bone imaging agents: skin testing to predict allergic response and a safe alternative agent.

We describe a severe systemic reaction which occurred in a patient on two occasions after i.v. injection of chemically related diphosphonate bone imaging agents. Skin testing showed reactivity to multiple commercially available diphosphonate compounds but no significant response to pyrophosphates. A subsequent pyrophosphate bone scan resulted in no adverse reaction. Severe systemic reactions to diphosphonates can occur, skin testing may prove useful in evaluating allergic reactions, and pyrophosphates appear to be a safe alternative agent in patients proven or suspected allergic to diphosphonates.

Adult↗

PubMed1980

Tc-99m HMDP (hydroxymethylene diphosphonate): a radiopharmaceutical for skeletal and acute myocardial infarct imaging. I. Synthesis and distribution in animals.

Technetium-99m hydroxymethylene diphosphonate (Tc-99M HMDP) is a new diphosphonate skeletal imaging agent. Animal studies show that Tc-99m HMDP has a higher uptake on bone and a more rapid clearance from the blood than any of the three technetium-labeled bone imaging agents in current use: Tc-99m methylene diphosphonate (DMP), Tc-99 (1-hydroxyethylidene) diphosphonate (HEDP), and Tc-99m pyrophosphate (PPi). On the basis of these animal studies, Tc-99m HMDP is a highly promising candidate for skeletal imaging.

Acute Disease↗

PubMed1981

A comparison of skeletal uptakes of three diphosphonates by whole-body retention: concise communication.

Twenty normal volunteers had measurements of 24-hr whole-body retention (WBR) of three structurally related Tc-99m-labeled phosphonate skeletal imaging agents: (1-hydroxyethylidene) diphosphonate (HEDP), methylene diphosphonate (MDP), and hydroxymethylene diphosphonate (HMDP). The average WBR values, reflecting skeletal uptake, were 18.4, 30.3, and 36.6%, respectively. These results clearly illustrate that slight alterations in diphosphonate molecular structure have a significant effect upon specificity for osseous tissue, and thus may affect skeletal image quality and the usefulness of the WBR technique in diagnosing metabolic bone disease.

Adult↗

PubMed1976

The alteration of osteoclast morphology by diphosphonates in bone organ culture.

Two diphosphonates alter the morphology of the osteoclast, as they inhibit the calcium45 release from bones stimulated to resorb by lipopolysaccharide. Disodium dichloromethylene diphosphonate was more potent than disodium ethane-1-hydroxy-1, 1-diphosphonate in both inhibiting 45calium release and altering osteoclast morphology. Alteration in the morphology of osteoclasts is associated with little or no change in the morphology of the surrounding non-osteoclast cells. These results indicate a specific morphological effect of diphosphonates on osteoclasts.

Animals↗

PubMed1989

Whole body and regional retention of Tc-99m-labeled diphosphonates with a whole-body counter: a study with normal males.

A collimated whole-body counter was used to measure the retention and distribution of radioactivity along the longitudinal axis of the body at several times during the 24 hours after the intravenous injection of 50 microCi of Tc-99m-diphosphonates. Whole-body retention (WBR) was measured together with regional uptakes in the following four areas: head, chest, bladder, and legs using two structurally related Tc-99m-diphosphonate skeletal imaging agents: 1-hydroxyethylidene diphosphonate (HEDP) and methylene diphosphonate (MDP). The average 24 hour WBR values in young males, reflecting skeletal uptake of these tracers, were 17.7 +/- 2.2% (n = 20) and 31.0 +/- 2.4% (n = 3), respectively. A model of skeletal clearance was developed using the sum of two exponentials. In normal volunteers the initial rapid clearance phase of both tracers had a half-time of about 1 hour, whereas the slower second phase clearance had a half-time of 22 hours with HEDP and 44 hours with MDP. The WBR is usually calculated for the entire body only at 24 hours, but with the improved spatial resolution of a collimated whole-body counter, regional measurements could potentially be done over shorter periods (6-8 hours) in order to simplify the procedure.

Bone Diseases↗

PubMed1975

Pyrophosphate and diphosphonates in skeletal metabolism. Physiological, clinical and therapeutic aspects.

Pyrophosphate and diphosphonates produce striking results on calcium metabolism in experimental animals and man. Compounds containing P-O-P- bonds (e.g. inorganic pyrophosphate [PP-ii1 or P-C-P bonds (diphosponates) inhibit both the formation and dissolution of calcium phosphate crystals in vitro. PP-i may have a physiological function in regulating calcification and bone turnover, and obnormalities in its metabolism may occur in some human diseases notably hypophosphatasia and pseudogout. Diphosphonates inhibit ectopic calcification, and slow down resorption and bone turnover in several experimental systems in vivo. They have helped in studies of various aspects of the regulation of calcium metabolism. The diphosphonate, disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) has been shown in clinical studies to be effective against ectopic calcification particularly in myositis ossificans progressiva and in disorders of increased bone resorption such as Paget's diseases and some types of osteoporosis. -99mTechnetium complexes of EHDP, PP-i and other polyphosphates have also recently been used successfully as bone scanning agents.

Animals↗

PubMed1975

Technetium-99m-methylene diphosphonate--a superior agent for skeletal imaging: comparison with other technetium complexes.

Methylene diphosphonate (MDP) was formulated as a complex of 99mTc for skeletal imaging. This agent was compared with three other bone-seeking technetium agents: ethane-1-hydroxy-1, 1-diphosphonate (EHDP), pyrophosphate, and polyphosphate. In tissue radioassay experiments in rodents, the technetium complexes of MDP and EHDP were similar, but skeletal concentration with both of these agents was higher than that with pyrophosphate or polyphosphate. The total-body retention of MDP and EHDP complexed with 95mTc was studied in beagle dogs for 35 days by excretion measurements and total-body counting and compared with polyphosphate and pertechnetate. The long-term retention was greater for MDP. The 5-day cumulative fecal excretion of 95mTc was low when administered as EHDP or polyphosphate complexes and negligible when administered as MDP complex. In six human volunteers the blood clearance of 99mTc-mdp was similar to that of 18F and significantly faster than that of 99mTc-EHDP. Pyrophosphate cleared from the blood much faster than polyphosphate but slower than the diphosphonates. The urinary excretion of the MDP complex was greater than for EHDP within the first 2-3 hr after injection. The 24-hr urinary excretion of pyrophosphate and polyphosphate complexes was not as complete as for the diphosphonates. All four 99mTc complexes proved satisfactory for clinical imaging studies. The MDP complex produced images of superior quality as early as 2 hr after administration, attributable to its more rapid clearance from the blood and soft tissues. On the contrary, a longer interval of 3-4 hr after injection was usually needed for 99mTc-EHDP; pyrophosphate and polyphosphate complexes regularly required a waiting period of 4 hr. Comparitive radiation dose estimates were made based on the available biologic distribution data for these 99mTc skeletal-localizing agents.

Animals↗

PubMed1989

NE-58095: a diphosphonate which prevents bone erosion and preserves joint architecture in experimental arthritis.

The rat adjuvant arthritis model, like human rheumatoid arthritis, is characterized by fulminating intra- and periarticular inflammation and bone lysis. This model was used to determine the effectiveness of a potent antiresorptive diphosphonate (NE-58095: monosodium [2-(3-pyridinyl) ethylidene] hydroxy diphosphonate) prophylactically in Lewis rats and therapeutically in Sprague-Dawley rats. Modified Freund's adjuvant (MFA) was injected into the tail of Lewis and Sprague-Dawley rats. Prophylactic treatment in Lewis rats [oral (PO): 14.8 mg/kg/day); subcutaneous (SC): 0.148 mg/kg/day] was begun on the day of MFA injection. A significant reduction in paw swelling was seen as early as day 12 after MFA injection with both oral and parenteral treatment. NE-58095 produced a reduction in paw swelling of 28, 39 and 61% on days 12, 17 and 24 respectively, as compared to the saline-treated MFA control. Bone lysis in the saline-treated MFA group was 85% of total possible incidence for 6 joint regions in the hind paws and 4 regions in the front paws at day 24. This resorption was reduced by 70% in the rats administered NE-58095 PO and SC at 24 days after MFA. In the therapeutic experiments with Sprague-Dawley rats, treatment with NE-58095 (SC: 0.148 mg/kg/day) was begun on day 14 after MFA injection, at which time significant paw swelling (greater than 0.5cc) had occurred. On day 25 (12 days of treatment), paw swelling was reduced 70% by NE-58095 treatment as compared to the saline-treated MFA controls. Histologically, the architecture of the tibio-tarsal joints in the saline-treated MFA rats was affected, in contrast to the NE-58095-treated MFA rats where the architecture of the joint was preserved. This new potent diphosphonate is not an anti-inflammatory compound by any of the classical tests and is effective both orally and parenterally. The mechanism by which this diphosphonate protects joint integrity is not clear but appears to be related to its ability to block bone resorption and the consequent inhibition of the diffusion into the joint space of calcium, chemotactic factors and cytokinas released from bone matrix, resulting in a quenching of the arthritic process.

Animals↗