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Etidronic Acid

A Review of its Pharmacological Properties and Therapeutic Efficacy in Resorptive Bone Disease

  • Drug Evaluation
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Summary

Synopsis

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 informing 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 bisphosphonate s requires that these compounds be continually compared and re-evaluated.

Pharmacodynamic Properties

Etidronic acid is adsorbed onto hydroxyapatite crystals in mineralised bone matrix, but it is currently thought that alterations in the number and activity of osteoclasts, together with other cellular mechanisms, are responsible for the anti-resorptive properties of this compound. It inhibits bone resorption both in vitro and in vivo, and appears to act preferentially on the axial skeleton. If administered continuously for prolonged periods at sufficiently high antiresorptive dosages, etidronic acid may impair the normal mineralisation of forming bone, as the dosage levels required to delay mineralisation are close to those used therapeutically. Recent data suggest, however, that this phenomenon may also be seen with the second generation bisphosphonate pamidronic acid at therapeutic dosages.

In patients with symptomatic Paget’s disease, etidronic acid decreases, or has no effect on, serum alkaline phosphatase (ALP) activity (a marker for osteoblastic activity), and serum calcium levels remain stable. Serum phosphate levels and renal tubular reabsorption of phosphate are increased, while serum creatinine, parathyroid hormone (PTH) and calcifediol (25-hydroxycholecalciferol) levels are generally unaffected.

In patients with hypercalcaemia of malignancy, etidronic acid reduces serum calcium levels when given intravenously at dosages of up to 500 mg/day for 3 to 7 days, the maximum effect being reached at approximately day 5. From the limited data available, serum creatinine levels and ALP activity appear unaffected, whereas urinary hydroxyproline (HDP) excretion (a marker of osteoclastic bone resorption) is reduced by approximately 50%.

Pharmacokinetic Properties

Etidronic acid is highly water soluble and its diffusion across lipid membranes is correspondingly poor. Oral bioavailability ranges from 1 to 10%. Between 20 and 50% of the orally absorbed dose becomes localised in bone, the remainder being excreted in the urine within 24 hours. The renal clearance of etidronic acid is 0.09 L/kg/h. The bisphosphonates have also been shown to accumulate in other tissues, including the stomach, liver, spleen and tracheal cartilage.

The plasma elimination half-life of etidronic acid is approximately 2 hours and the volume of distribution 0.3 to 1.3 L/kg. Etidronic acid has a high affinity for bone, where its elimination half-life exceeds 1 year. Animal studies with radiolabelled etidronic acid indicate that intermittent cyclic courses over 3 years would result in skeletal retention of 25 to 50 times the daily absorbed dose.

Etidronic acid has been shown to interfere with the skeletal binding of diagnostic radioisotopes such as technetium-labelled methylene diphosphonate (99Tcm-MDP).

Therapeutic Use

Sustained suppression of serum ALP activity and urinary HDP excretion to normal levels may be achieved in up to 76% of patients with Paget’s disease of bone after a single 6-month course of etidronic acid 5 to 20 mg/kg/day administered orally. These improvements may be maintained in some patients for up to 5 years. Subjective pain scores (bone, joint and mixed pain) are reduced to a clinically significant extent in a majority of patients, even in the presence of osteoarthritis, and these reductions persist for a similar period. No radiological evidence of improvement in skeletal structure is evident, however, after treatment with etidronic acid 5 to 20 mg/kg/day for periods of up to 5 years. Treatment of Paget’s disease with etidronic acid at the higher dosage range of 10 to 20 mg/kg/day has been associated with delayed mineralisation, indicated by osteoid seam widening, but these effects are not seen at the lower dosage of 5 mg/kg/day.

Data from a limited number of sequential studies indicate that oral etidronic acid 7 to 14 mg/kg/day for 6 months is superior to calcitonin ≤160 MRC units daily in reducing serum ALP levels and urinary HDP excretion in Paget’s disease. When etidronic acid is given together with synthetic human calcitonin, clinical and biochemical effects are similar to those of calcitonin alone. Clinical benefit may, however, be obtained more rapidly with combined treatment. Similar reductions in serum AP levels have been observed in patients with Paget’s disease after treatment with etidronic acid 5 to 20 mg/kg/day and clodronic acid 800 to 1600 mg/day.

Etidronic acid 7.5 mg/kg/day in combination with intravenous rehydration and furosemide 40 to 80 mg/day has shown superior efficacy to hydration + diuretic alone in the management of hypercalcaemia of malignancy. In patients resistant to rehydration, intravenous etidronic acid 7.5 mg/kg/day for 3 to 5 days produced normocalcaemia in 31 to 43% of patients. However, the drug was less effective in this respect, when given orally or intravenously, than single intravenous doses of pamidronic acid 30 to 60mg, clodronic acid 600mg or plicamycin 25 µg/kg, or intravenous gallium nitrate 200 mg/m /day for 5 days.

The majority of clinical studies involving etidronic acid in osteoporosis have involved postmenopausal women, with much interest being focused on cyclic or coherence (ADFR) regimens. Etidronic acid 400 mg/day orally for 14 days increased bone mineral density (BMD) of the lumbar vertebrae when given either as part of an ADFR regimen or cyclically without an activator. Treatment for 2 years has resulted in BMD increases versus baseline of up to 15.7%; this contrasts with unchanged or reduced BMD after placebo treatment or calcium supplementation alone. Published trials have also indicated a favourable effect of etidronic acid on vertebral fracture rate (VFR). Results of studies comparing etidronic acid with hormone replacement therapy (HRT) are equivocal. Recent data have suggested a preventative effect of cyclic courses of etidronic acid on corticoste-roid-induced osteoporosis.

Etidronic acid 10 to 20 mg/kg/day orally has been shown to be effective in reducing the incidence of heterotopic ossification and its ensuing complications in both neurological and post-surgical patients. Orthopaedic patients benefit from therapy initiated 4 to 6 weeks before surgery and continued for 3 months post-operatively; those with spinal cord injury require treatment within 60 days of trauma. Etidronic acid does not prevent ectopic bone formation in these patients, but delays its mineralisation, thus allowing patients to mobilise fully before heterotopic lesions are able to consolidate.

Tolerability

Clinical studies have indicated that etidronic acid is well tolerated by the majority of patients at dosages of up to 20 mg/kg/day. Gastrointestinal adverse events are most commonly reported in the literature, usually after oral therapy. Taste disturbance, often manifesting as a metallic taste sensation, has been reported by patients receiving intravenous etidronic acid for hypercalcaemia of malignancy and tumour-induced bone disease; normal taste perception returns rapidly after cessation of treatment.

No clinically significant abnormalities in hepatic function or serum biochemistry attributable to etidronic acid therapy have been documented. Renal tubular reabsorption of phosphate is increased, but this appears to be of no clinical consequence. Rare instances of renal failure have been attributed to etidronic acid given as high-dosage intravenous therapy for hypercalcaemia of malignancy (bolus or rapid infusion of up to 1g daily).

In patients with Paget’s disease undergoing treatment with etidronic acid, development of, or increase in, bone pain at pagetic sites has occurred in 1 to 10% of patients, the effect being dose-related and associated with adverse effects on bone mineralisation.

Histomorphometry has failed to demonstrate defective mineralisation, and desirable effects on bone remodelling have been observed, after up to 7 years’ cyclical treatment with oral etidronic acid 400 mg/day in women with established postmenopausal osteoporosis.

Dosage and Administration

Patients with Paget’s disease should be treated with an initial oral etidronic acid dosage of 5 mg/kg/day for up to 6 months. Dosages above 10 mg/kg/day should be reserved for patients in whom there is an overriding need to suppress bone turnover and should not exceed 3 months’ duration; it is inadvisable to give more than 20 mg/kg/day.

Intravenous dosages of 7.5 mg/kg/day following adequate rehydration are effective when given for 3 days in the management of malignant hypercalcaemia: the dose should be infused over at least 2 hours. Dosage reduction may be advisable in the presence of impaired renal function. Oral etidronic acid 20 mg/kg/day for up to 30 days may be used to maintain normocalcaemia, with the first dose administered on the day following the last intravenous dose.

Established vertebral osteoporosis may be treated with etidronic acid 5 to 10 mg/kg/day (usual dosage 400 mg/day) orally for 14 days, followed by a 76-day period of calcium supplementation, with this cycle repeated for up to 3 years.

For the prevention of heterotopic ossification following total hip replacement, etidronic acid 20 mg/kg/day should be given orally from 1 month before to 3 months after surgery, and spinal cord injury patients may benefit from 20 mg/kg/day for 2 weeks, followed by 10 mg/kg/day for a further 10 weeks. Treatment should start as soon as possible after injury.

Oral etidronic acid should not be administered with food or dairy products; mineral supplements and antacids will also impair gastrointestinal absorption and the drug should therefore be taken in the middle of a 4-hour fast. It may be taken as a single daily dose, although divided doses may be given if adverse gastrointestinal effects occur.

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    Christopher J. Dunn, Andrew Fitton & Eugene M. Sorkin

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Various sections of the manuscript reviewed by:H. Fleisch, Department of Pathophysiology, University of Berne, Berne, Switzerland; S.T. Harris, Departments of Medicine and Radiology, University of California, San Francisco, California, USA; C. Hasling, Department of Internal Medicine, Odder Centralsygehus, Odder, Denmark; J.A. Kanis, Sheffield Metabolic Bone Unit, University of Sheffield, Sheffield, England; A.A. Licata, Cleveland Clinic Foundation, Cleveland, Ohio, USA; D.E. Meier, Department of Geriatrics, Mount Sinai Medical Center, New York, New York, USA; S.H. Ralston, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, Scotland; J.C. Renier, Service de Rhumatologie, Centre Hospitalier Régional et Universitaire, Angers, France; R.G.G. Russell, Department of Human Metabolism and Clinical Biochemistry, University of Sheffield, Sheffield, England; F.R. Singer, John Wayne Cancer Institute, Santa Monica, California, USA; N.B. Watts, Section of Internal Medicine, Emory Clinic, Atlanta, Georgia, USA; C. Wüster, Department of Internal Medicine I, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany.

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Dunn, C.J., Fitton, A. & Sorkin, E.M. Etidronic Acid. Drugs & Aging 5, 446–474 (1994). https://doi.org/10.2165/00002512-199405060-00006

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