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PubMedDate not supplied

Spontaneous fractures in a patient treated with low doses of etidronic acid (disodium etidronate).

The recommended regimen of etidronic acid (disodium etidronate) for the treatment of Paget's disease of bone is 5mg/kg/day for a period of less than six months. There have, however, been reports of impaired mineralisation of bone and concern that the risk of fracture is increased with this dosage. We report a patient with Paget's disease in whom fractures occurred through pagetic and non-pagetic bone which appeared to be causally related to treatment with lose doses of etidronic acid. The osteomalacia resolved when etidronic acid was discontinued.

Aged↗
PubMed2000

Bisphosphonate prodrugs: synthesis and in vitro evaluation of alkyl and acyloxymethyl esters of etidronic acid as bioreversible prodrugs of etidronate.

The synthesis and preliminary evaluation of novel alkyl and acyloxymethyl esters of etidronic acid as etidronate prodrugs is reported. Tetramethyl ester of etidronic acid was found be isomerized at pH 7.4 and P-C-P bridge was rearranged to P-C-O-P. This unwanted process was prevented via acylation of the bridging carbon's alcohol group. Acylation showed to be stable if one or more phosphonic OH- groups were substituted. However, when none of the phosphonic OH- groups were substituted, the acylation was chemically hydrolysed and the parent drug was released. This finding was successfully applied in the design of tetrapivaloyloxymethyl ester of acetylated etidronic acid which released etidronic acid via enzymatic (first step) and chemical (second step) hydrolysis in liver homogenate. However, the corresponding tri-substituted pivaloyloxymethyl ester having adequate water-solubility and lipophilicity (logP(app) 0.6 at pH 7.4), is probably the most potential prodrug candidate reported to enhance the oral bioavailability of etidronate.

Animals↗
PubMed1999

Etidronic acid and steroid therapy: new indication. No proven impact on fractures.

(1) Etidronic acid (disodium etidronate) has a new licensed indication in the prevention of bone loss due to steroid therapy. (2) Three randomised, double-blind placebo-controlled trials have been done in this setting. The benefit of etidronic acid has been shown only on the basis of lumbar bone density (a surrogate end point) and only in women. (3) There is no concrete evidence that etidronic acid is any more effective than a placebo in reducing the risk of fracture in patients on steroid therapy. Similarly, in the absence of comparative trials there is no proof that etidronic acid is any more effective than hormone replacement therapy in postmenopausal women.

Calcium↗
PubMed2006

Effect of etidronic acid on arterial calcification in dialysis patients.

BACKGROUND: Bisphosphonate drugs, including etidronic acid, are effective agents for the treatment of osteoporosis and may reduce arterial calcification. The aim of this randomised control trial was to characterise the effect of etidronic acid on arterial calcification in patients undergoing chronic haemodialysis. METHODS: Patients undergoing chronic haemodialysis were assigned to one of two groups by a simple randomisation method: an etidronic acid group (n = 8; 400 mg/day for 24 weeks) and a control group (n = 6; no etidronic acid therapy). Serum calcium, phosphate, calcium-phosphate product, alkaline phosphatase, lactate dehydrogenase, activated colecalciferol and parathyroid hormone levels were measured at baseline and then at 4-weekly intervals thereafter. RESULTS: Calcification scores of the coronary arteries and the thoracic and abdominal aorta were determined by volume-correcting data collected by a multi- detector-row computerised tomographic scanner at baseline, at 6 months and at 1 year. Two patients in the etidronic acid group were excluded from the final analysis because of medical complications. The remainder of the patients (n = 6) showed no significant temporal changes in serum levels of assessed parameters. While no significant temporal changes in coronary calcification score were observed in either group, the mean aortic calcification score significantly decreased over time from 1000 +/- 460mm(3 )at baseline to 970 +/- 580mm(3) at the completion of treatment and 350 +/- 180mm(3) at 1 year (p = 0.009), corresponding to a mean percentage decrease of -64.1% (range -86.5% to -50.1%). By contrast, in the control group, the mean aortic calcification score significantly increased with time from 1460 +/- 1280mm(3) to 1510 +/- 1150mm(3) at the completion of treatment and 2070 +/- 1200mm(3) at 1 year (p = 0.006), corresponding to a mean percentage change in the calcification score of +130.0% (range 2.1-414%). CONCLUSION: Etidronic acid markedly reduced aortic calcification in patients with end-stage renal disease undergoing chronic haemodialysis. The effect of this agent on aortic calcification may attenuate the increase in aortic stiffness and result in improved long-term outcomes in patients undergoing chronic haemodialysis.

Aged↗
PubMed1994

Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease.

Etidronic acid is an orally and intravenously active bisphosphonate, which is believed to inhibit resorption of bone via a number of cellular mechanisms, including alteration of osteoclastic activity. In studies of patients with symptomatic Paget's disease, etidronic acid 5 to 20 mg/kg/day administered orally rapidly decreased the biochemical indices of bone turnover. Mineralisation defects in forming bone may be avoided by the use of an initial dosage of 5 mg/kg/day for up to 6 months; dosages above 10 mg/kg/day should be limited to 3 months' duration, and dosages greater than 20 mg/kg/day should be avoided. Although 3-day intravenous therapy with etidronic acid 7.5 mg/kg/day has shown superior efficacy to rehydration and forced diuresis in the management of hypercalcaemia of malignancy, the efficacy of the drug is lower than that of the newer bisphosphonates, pamidronic acid and clodronic acid. Clinical studies involving postmenopausal women with established osteoporosis have indicated that oral etidronic acid 400 mg/day for 14 days as part of a 90-day cycle, repeated for up to 3 years, increases the bone mineral density (BMD) of the lumbar vertebrae and appears to reduce the incidence of vertebral fracture. Published data suggest that etidronic acid shows similar efficacy to hormone replacement therapy (HRT) in these respects. The above dosage also appears to be effective in preventing corticosteroid-induced osteoporosis when administered as part of an intermittent, cyclical regimen. Etidronic acid in higher dosages (10 to 20 mg/kg/day orally) is effective in reducing the incidence of heterotopic ossification and its ensuing complications in both neurological and post-surgical patients. Etidronic acid is well tolerated by the majority of patients, with gastrointestinal complaints reported most commonly, but tends to delay the normal mineralisation of forming bone when administered continuously at higher dosages for prolonged periods. This is of little consequence where short term treatment is involved, but may be detrimental to those patients receiving longer courses of therapy. This effect may be minimised or avoided by using the lowest effective dosage for as short a time as possible (as in the above recommendations for Paget's disease), or by the use of intermittent cyclical therapy (as in the management of osteoporosis). Etidronic acid therefore retains a role in the management of resorptive bone disease, particularly in the treatment of Paget's disease, the prevention of heterotopic ossification, and as a second-line option in postmenopausal osteoporosis. However, the development of newer bisphosphonates requires that these compounds be continually compared and re-evaluated.

Bone Diseases↗
PubMed1983

[Etidronic acid therapy in Paget's disease of bone].

Treatment of Paget's disease of bone was done in 32 patients using monotherapy with disodium etidronate (Diphos). A further 19 patients underwent combined treatment with etidronate and human calcitonin. Both monotherapy and combined treatment led to marked regression of disease activity in most patients as measured be decreased activity of alkaline phosphatase. In most cases this coincided with improvement of complaints. In two cases with initial monotherapy and in six with combined treatment success of treatment remained unsatisfactory. The latter group comprised patients with very serious illness. Our experience suggests that etidronic acid is an effective and well tolerated drug relatively free of side-effects for the treatment of Paget's disease of bone.

Alkaline Phosphatase↗
PubMed2000

[Efficiency of etidronic acid in the case of cutaneous radiocontamination by actinid elements: in vitro evaluation].

Ethane 1 hydroxy 1.1. biphosphonate (EHBP) is a medicine named Didronel, which inhibits bone resorption in the case of Paget's disease. This molecule could offer a new application in radiotoxicology. Our works describe its efficiency as decontaminating agent in uranium and plutonium cutaneous radiocontamination. Its effect on uranium and plutonium is demonstrated by two in vitro techniques using human cutaneous explants. Both techniques are usually used in dermopharmacology to estimate the action of topic drugs.

Chelating Agents↗
PubMed2004

Management of osteoporosis in adults with cystic fibrosis.

Cystic fibrosis (CF) is the most common genetic disease that causes respiratory failure within the Caucasian population. The life span of patients with CF has gradually increased from a median of 2 years of age to >30 years. Concurrent with this increased lifespan, a variety of other nutritional, endocrine and bone issues have been recognised. Decreased absorption of fat-soluble vitamins (D and K in particular) because of pancreatic insufficiency, altered sex hormone production, chronic inflammation, a lack of physical activity, glucocorticoid treatment and an intrinsic hyper-resorptive bone physiology are some of the factors that contribute to the prominence of bone disease within the CF population. In some series, three-quarters of adult patients with CF have osteopenia or osteoporosis. Lung transplantation is one viable treatment for patients with end-stage CF, which requires a lifetime of antirejection medication. Immunosuppressant therapies have a detrimental effect on bone mineral density (BMD). To combat the multifactorial nature of CF-related bone disease, advances in nutritional and vitamin supplementation, and anti-resorptive and anabolic therapies have evolved. Chronic vitamin D depletion contributes to bone disease in the CF population. The isoform of vitamin D that is the best and safest supplement, with the lowest cost, has yet to be identified. However, it is clear that many patients with CF who receive the standard of care (i.e. two daily combination vitamin A, D, E and K tablets [ADEKs]) may still be vitamin D-deficient. More aggressive supplementation needs to be individualised, with close monitoring of serum 25-hydroxyvitamin D levels. Similarly, routine calcium supplementation may be important, and evidence is accumulating that vitamin K also plays an important role in maximising and maintaining BMD. Early recognition and treatment of delayed puberty in adolescents and hypogonadism in adults with hormone replacement therapy is recommended to maintain BMD in patients with CF. Bisphosphonates, including pamidronic acid, etidronic acid and alendronic acid, reduce bone resorption by inhibiting the recruitment and function of osteoclasts. Pamidronic acid is beneficial in improving BMD in CF patients before and after transplantation. Bisphosphonate therapy and minimisation of glucocorticoid dosage have been shown to be efficacious in glucocorticoid-induced osteoporosis. Teriparatide is the first US FDA-approved anabolic growth agent for bone, and has been shown to increase BMD and decrease fracture incidence in postmenopausal women. Teriparatide may offer a new avenue for treating bone disease in CF since many patients may have poor bone formation as well as accelerated bone breakdown. Numerous clinical trials are underway to optimise treatment of CF osteoporosis.

Adult↗
PubMed2004

Determination of bisphosphonates by ion chromatography-inductively coupled plasma mass spectrometry.

An ion chromatography-inductively coupled plasma mass spectrometry (IC-ICP-MS) was introduced in the analysis of bisphosphonates. Two compounds (alendronic acid and etidronic acid) were separated on a Dionex AS-7 anion-exchange column with dilute nitric acid employed as the mobile phase. The analytes were detected at m/z 31, as they contain phosphorus. The detection limits achieved were 0.20 mg l(-1) for alendronic acid and 0.05 mg l(-1) for etidronic acid. Since the determination of phosphorus by ICP-MS is difficult due to polyatomic interferences at m/z 31 (15N16O+, 14N16O1H+, and 12C1H(3)16O+), a detailed study of the influence of plasma parameters on phosphorus and background signal was performed.

Chromatography, Liquid↗
PubMed1996

Corticosteroid-induced bone loss. Prevention and management.

Osteoporosis is one of the most serious adverse effects experienced by patients receiving long term corticosteroid therapy. Bone loss occurs soon after corticosteroid therapy is initiated and results from a complex mechanism involving osteoblastic suppression and increased bone resorption. There are a number of factors that may increase the risk of corticosteroid-induced osteoporosis [smoking, excessive alcohol (ethanol) consumption, amenorrhoea, relative immobilisation, chronic obstructive pulmonary disease, inflammatory bowel disease, hypogonadism in men, organ transplantation]. The initial assessment of patients about to start taking corticosteroids should include measurement of spinal bone density, urinary calcium level and plasma calcifediol (25-hydroxycholecalciferol) level; serum testosterone levels should also be measured when hypogonadism is suspected. Many different drugs have been used to prevent osteoporosis in patients receiving long-term corticosteroid therapy, including thiazide diuretics, cholecalciferol (vitamin D) metabolites, bisphosphonates, calcitonin, fluoride, estrogens, anabolic steroids and progesterone. At present, however, published studies have failed to demonstrate a reduction in the rate of fracture using different preventive pharmacological therapies in patients being treated with corticosteroids on a continuous basis. Among the drugs studied, bisphosphonates (pamidronic acid and etidronic acid) and calcitonin appear to be effective in increasing bone density. Cholecalciferol preparations have been reported to be effective in some, but not all, studies. Limited data have shown positive results with thiazide diuretics, estrogen, progesterone and nandrolone. When treating patients with corticosteroids, the lowest effective dose should be used, with topical corticosteroids used whenever possible. Auranofin may be considered in patients with corticosteroid-dependent asthma. Patients should take as much physical activity as possible, maintain an adequate daily intake of calcium (1000 mg/day0 and cholecalciferol (400 to 800 U/day), stop smoking and avoid excessive alcohol intake. It is important to detect and treat hypogonadism in men, if present, and to replace gonadal hormones in postmenopausal women or amenorrhoeic premenopausal women, and to detect and correct cholecalciferol deficiency. A thiazide diuretic should be considered if hypercalciuria is present (urinary calcium excretion in excess of 4 mg/kg/day). High-risk patients and those with established osteoporosis should be treated with bisphosphonates (cyclical etidronic acid or intravenous pamidronic acid), nasal calcitonin, or calcifediol or calcitriol. Patients receiving cholecalciferol preparations should be carefully monitored for hypercalciuria and hypecalcaemia.

Adrenal Cortex Hormones↗
PubMed1997

An economic evaluation of tiludronic acid treatment in Paget's disease of bone.

The objective of this study was to evaluate the long term comparative outcome of intermittent courses of therapy with low-dosage tiludronic acid (400 mg/day) versus etidronic acid in patients with Paget's disease of bone. The long term outcome was evaluated by means of a model, as the number of complications avoided during a 5-year period. Only major complications were considered (fractures of long bones, spinal cord dysfunction, osteoarthritis of the hip), which can be cured by adequate medical intervention, and may thus be valued in terms of direct costs. Deafness was not considered and was not valued. The various additional direct costs incurred (treatment and follow-up) and avoided (complications avoided) were assessed using an extrapolation model, based on the results of a clinical study. A standard costing methodology was used, according to the patterns of care currently in use in France. Costs were calculated from a societal perspective, including social security and private insurance fund reimbursements, and out-of-pocket expenses. These were estimated in French francs (F: 1994 values). The estimated mean treatment cost per patient for the treatment of Paget's disease and its complications over a 5-year period was F34,198 with etidronic acid, and F30,754 to F36,422 with tiludronic acid, depending on whether an optimistic or a conservative view of the efficacy of tiludronic acid was assumed. Despite its higher acquisition cost, the use of tiludronic acid was less expensive in the treatment of Paget's disease and its complications, compared with the use of etidronic acid, when an optimistic view of the efficacy of tiludronic acid was assumed.

Adult↗
PubMed1990

Advances in the management of Paget's disease of bone.

The advent of potent new bisphosphonates (diphosphonates) now makes it possible to restore and maintain normal bone turnover in many patients with Paget's disease of bone (osteitis deformans). This has necessitated a reappraisal of the indications for treatment, the ways in which disease activity and response are assessed, as well as the place of existing therapies. Measurements of urinary hydroxyproline and serum alkaline phosphatase remain the most useful markers of disease activity. Pyridinium crosslinks may prove to be more specific than hydroxyproline in the assessment of bone resorption but osteocalcin has been disappointing in monitoring the effect of treatment on bone formation. Etidronic acid (disodium etidronate), the first bisphosphonate introduced for clinical use, is a potent inhibitor of osteoclastic bone resorption but its potential is limited by the development of defective mineralisation with high dosage (10 to 20 mg/kg/day). The newer bisphosphonates, clodronic acid (clodronate) and pamidronic acid (pamidronate, APD), are free from this problem and appear able to control a wide range of disease activity. A small number of patients appear resistant to the agents but the underlying mechanism is unclear. The efficacy and safety of these bisphosphonates makes it likely that the threshold for treating asymptomatic patients will fall in the hope of preventing long term complications. These developments will lead to a reappraisal of the role of calcitonin which can now be administered by both the parenteral and intranasal routes. One focus of interest will be on the quality of the bone laid down during treatment. Meticulous radiographic studies have shown that calcitonin improves bone architecture and this may have particular relevance to the treatment of lytic disease. The relative merits of the different forms of therapy for Paget's disease need further evaluation, particularly with respect to the identification of specific advantages of individual drugs.

Humans↗
PubMed2002

Food-drug interactions.

Interactions between food and drugs may inadvertently reduce or increase the drug effect. The majority of clinically relevant food-drug interactions are caused by food-induced changes in the bioavailability of the drug. Since the bioavailability and clinical effect of most drugs are correlated, the bioavailability is an important pharmacokinetic effect parameter. However, in order to evaluate the clinical relevance of a food-drug interaction, the impact of food intake on the clinical effect of the drug has to be quantified as well. As a result of quality review in healthcare systems, healthcare providers are increasingly required to develop methods for identifying and preventing adverse food-drug interactions. In this review of original literature, we have tried to provide both pharmacokinetic and clinical effect parameters of clinically relevant food-drug interactions. The most important interactions are those associated with a high risk of treatment failure arising from a significantly reduced bioavailability in the fed state. Such interactions are frequently caused by chelation with components in food (as occurs with alendronic acid, clodronic acid, didanosine, etidronic acid, penicillamine and tetracycline) or dairy products (ciprofloxacin and norfloxacin), or by other direct interactions between the drug and certain food components (avitriptan, indinavir, itraconazole solution, levodopa, melphalan, mercaptopurine and perindopril). In addition, the physiological response to food intake, in particular gastric acid secretion, may reduce the bioavailability of certain drugs (ampicillin, azithromycin capsules, didanosine, erythromycin stearate or enteric coated, and isoniazid). For other drugs, concomitant food intake may result in an increase in drug bioavailability either because of a food-induced increase in drug solubility (albendazole, atovaquone, griseofulvin, isotretinoin, lovastatin, mefloquine, saquinavir and tacrolimus) or because of the secretion of gastric acid (itraconazole capsules) or bile (griseofulvin and halofantrine) in response to food intake. For most drugs, such an increase results in a desired increase in drug effect, but in others it may result in serious toxicity (halofantrine).

Anti-Infective Agents↗
PubMed2002

Modern therapy for Paget's disease of bone: focus on bisphosphonates.

There has been a dramatic change in the therapeutic approach to patients with Paget's disease of bone over the last 40 years. In the 1960s, only symptomatic therapy could be given, with control of pain the main objective. Analgesics and nonsteroidal anti-inflammatory drugs were the most commonly used agents. From 1968 onwards, antiosteoclastic agents became available, including calcitonin, plicamycin (mithramycin) and etidronate (etidronic acid), a first-generation bisphosphonate. Limitations with these agents, including potentially deleterious effects on bone mineralization with etidronate (etidronic acid), has cleared the way for increasingly potent second- and third-generation bisphosphonates, including clodronate (clodronic acid), pamidronate (pamidronic acid), alendronate (alendronic acid) and risedronate (risedronic acid). Even more potent bisphosphonates will become available in the near future. With the newer bisphosphonates, there is some hope for long-term remission (if not definitive healing) of pagetic lesions, as well as prevention of long-term complications in both symptomatic and asymptomatic patients. Thus, indications for therapy have been extended to include younger patients to prevent bone deformity of the limbs and skull, leading to secondary osteoarthritis, facial deformities and potentially to sarcoma transformation; as well as to elderly patients to prevent bone fragility, leading to fracture, and pagetic vascular steal syndromes. The increased potency and longer duration of action of newer bisphosphonates more than compensates for their marginally increased cost compared with older bisphosphonates.

Animals↗