Professional Information

Etidronate (Systemic)

VA CLASSIFICATION
Primary: HS303
Secondary: HS302

Commonly used brand name(s): Didronel.

Another commonly used name is
EHDP .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Bone resorption inhibitor—

antihypercalcemic—

Indications

Accepted

Paget's disease of bone (treatment)—Oral etidronate is indicated for the treatment of symptomatic ^{09} Paget's disease (osteitis deformans), characterized by abnormal and accelerated bone turnover ^{09} in one or more bones. Signs and symptoms may include bone pain, deformity, and/or fractures; increased concentrations of serum alkaline phosphatase and/or urinary hydroxyproline; neurologic disorders associated with skull lesions and vertebral deformities; and elevated cardiac output and other vascular disorders associated with increased vascularity of bones. ^{01}
—Although studies have not been done on etidronate's effects in asymptomatic ^{09} Paget's disease, treatment may be considered for such patients if extensive involvement of the skull or vertebral column might lead to neurologic damage; if extensive involvement of weight-bearing bones threatens their integrity; or if juxta-articular involvement threatens the integrity of adjacent joints. ^{31}

Ossification, heterotopic (prophylaxis and treatment)—Oral etidronate is indicated for the prevention and treatment of heterotopic ossification (myositis ossificans—circumscripta ^{09}, progressiva, or traumatica; ectopic calcification; periarticular ossification; or paraosteoarthropathy) following total hip replacement or caused by spinal cord injury. ^{01} Heterotopic ossification is characterized by metaplastic osteogenesis, and may be accompanied by localized inflammation and pain, and elevated skin temperature or redness. Also, loss of joint function or reduction in range of motion ^{09} may occur when tissues near joints are involved. ^{01}

Hypercalcemia, associated with neoplasms (treatment adjunct)—Parenteral etidronate is indicated as adjunctive therapy for the treatment of hypercalcemia of malignancy that is inadequately managed by dietary changes and/or oral hydration alone. ^{32} It is used in conjunction with adequate saline hydration and with ``high ceiling'' or loop diuretics, such as bumetanide, ethacrynic acid, and furosemide. Limited clinical study results show that ^{14} oral etidronate may be used in some patients ^{18} after the last dose of etidronate infusion to maintain clinically acceptable serum calcium concentrations and to prolong normocalcemia. ^{10}

Unaccepted
Hypercalcemia caused by hyperparathyroidism, where increased tubular reabsorption of calcium may be a factor in the hypercalcemia, is refractory to parenteral etidronate. ^{32}

Note: Oral etidronate is presently being used experimentally in the U.S. to treat osteoporosis in adults. A small increase in bone mineral density has been noted. ^{28} ^{29} Some studies with continuous dosing of etidronate have found abnormal mineralization of osteoid and microfractures that might potentially result in increased susceptibility to fractures, especially nonvertebral fractures. ^{26} ^{27} Further studies are needed to determine the safety profile and dosing information. ^{26} ^{27} ^{30}

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    249.99

Mechanism of action/Effect:

Although the exact mechanism is not completely understood, etidronate chemisorbs to calcium phosphate surfaces of calcium hydroxyapatite crystals and their amorphous precursors, and, in vitro , blocks the aggregation, growth, and mineralization ^{17} of the crystals. ^{32} A similar process is believed to be responsible in vivo for retarding the mineralization and growth of heterotopic ossification. This process may also be responsible for retarding bone resorption, and, secondarily, for retarding the accelerated rate of bone turnover in Paget's disease.

Paget's disease—Etidronate induces a reduction of bone resorption, which is accompanied by a reduction in the number of osteoclasts. Secondarily, coupled bone formation is reduced, which is associated with a reduction in the number of osteoblasts. New bone formed following the reduction in bone turnover is histologically more normal. Lamellar bone is formed, and the marrow becomes less vascular and fibrotic. ^{09} Etidronate reduces serum alkaline phosphatase and urinary hydroxyproline concentrations, reduces radionuclide uptake at pagetic lesions, decreases elevated cardiac output by reducing bone vascularity, and reduces elevated skin temperature over pagetic lesions. The incidence of pagetic fractures may be reduced when etidronate is administered intermittently over a period of years ^{09}.

Heterotopic ossification—Etidronate slows the progression of immature bone lesions, thus reducing the severity of the disease.

Hypercalcemia of malignancy—Bone resorption is increased in the presence of neoplastic tissue. Etidronate inhibits abnormal bone resorption and reduces the flow of calcium from the resorbing bone into the blood, effectively decreasing total and ionized serum calcium. When kidney function is adequate for the fluid load, hydration with saline increases urine output and the use of diuretics increases the rate of calcium excretion. ^{10}

Duration of therapeutic effect

Paget's disease—Possibly up to a year or more after discontinuation of therapy.

Heterotopic ossification—Several months after discontinuation of therapy.

Hypercalcemia—Clinical studies indicate a median duration of normocalcemia of 11 days. ^{14}

Absorption:

Lower doses (5 mg per kg of body weight (mg/kg) a day)—1% (average).

Higher doses (10 to 20 mg per kg a day)—2.5 to 6% (average). ^{06}

Distribution:

Approximately half of absorbed dose is chemically adsorbed to bone, presumably upon hydroxyapatite crystals, ^{06} in areas of elevated osteogenesis. ^{01}

Biotransformation:

None. ^{31}

Half-life:

Elimination—Approximately 50% of the absorbed/infused ^{14} dose is eliminated from the body ^{14} within 24 hours. The remainder is presumably chemisorbed to bone ^{20} and slowly eliminated.

Plasma—5 to 7 hours. ^{10}

Onset of action:

Paget's disease—May be observed after 1 month of treatment; initially observed as a reduction in urinary hydroxyproline.

Hypercalcemia—Reductions in urinary calcium excretion, which accompany reductions in bone resorption, ^{14} may become apparent after 24 hours. ^{10}

Time to peak effect

Hypercalcemia—Decreases in serum calcium are maximal on the day following the third infusion, ^{20} in most patients.

Elimination:
    Absorbed dose—50% excreted intact in the urine via the kidneys.
    Unabsorbed dose—Intact in the feces.

Precautions to Consider

Carcinogenicity

Long-term studies in rats have shown no evidence of carcinogenicity. ^{31} ^{32}

Pregnancy/Reproduction

Pregnancy—

For oral etidronate

Adequate and well-controlled studies in humans have not been done.

Studies in rats and rabbits administered oral doses up to 5 times the maximum human dose have shown no evidence of impaired fertility or harm to the fetus. However, studies in rats administered doses 22 times the maximum human dose of etidronate have shown a decrease in live fetuses. ^{31}

FDA Pregnancy Category B. ^{31}

For parenteral etidronate

Reproductive studies have not been done in either animals or humans. Rats administered large parenteral doses showed skeletal malformations, which were attributed to the pharmacologic action of the drug ^{01} ^{10}

FDA Pregnancy Category C. ^{10} ^{32}

Breast-feeding

It is not known if etidronate is distributed into breast milk. However, problems in humans have not been documented. ^{31} ^{32}

Pediatrics

Appropriate studies have not been performed in the pediatric population. However, in children treated for heterotopic ossification or soft tissue calcifications at doses of 10 mg or more per kg of body weight a day for prolonged periods (approaching or exceeding a year) ^{20}, signs of a rachitic syndrome were infrequently reported. Epiphyseal radiologic changes associated with retarded mineralization of new osteoid and cartilage have been reversible upon discontinuation of etidronate. ^{19} ^{31}

Geriatrics

Appropriate studies have not been performed in the geriatric population. However, elderly patients may be more prone to overhydration when treated with parenteral etidronate in conjunction with hydration therapy. Careful monitoring of fluid and electrolyte status is recommended. ^{14}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Antacids containing calcium, magnesium, or aluminum or^{31}
» Foods containing large amounts of calcium, such as milk or other dairy products or^{31}
» Mineral supplements or other medications containing calcium, iron, magnesium, or aluminum^{31}    (concurrent use may prevent absorption of oral etidronate; patients should be advised to avoid using within 2 hours of etidronate)

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Technetium Tc 99m medronate or
Technetium Tc 99m oxidronate or
Technetium Tc 99m pyrophosphate^{28}^{29}^{30}    (etidronate may theoretically ^{14} interfere with bone uptake of these diagnostic agents; clinical significance is unknown ^{13} ^{14})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problem exists:

For hypercalcemia:
» Renal function impairment when serum creatinine is 5 mg per dL or greater    (kidney function may be inadequate for the increased fluid load and the excretion of etidronate ^{10} ^{32})

Risk-benefit should be considered when the following medical problems exist
» Bone fractures, especially of long bones    (mineralization of osteoid laid down during the bone accretion process may be retarded because of the inhibition of hydroxyapatite crystal growth; delay or interruption of etidronate treatment for Paget's disease may be necessary until callus formation and calcification are evident ^{01})

» Cardiac failure    (overhydration should be avoided with use of parenteral etidronate in patients with cardiac failure ^{10})

» Enterocolitis    (risk of diarrhea is increased, particularly at higher doses ^{01} ^{31})

Hyperphosphatemia    (high doses of oral etidronate may increase the tubular reabsorption of phosphate; occurs less frequently with parenteral therapy ^{31})

Hypocalcemia or
Hypovitaminosis D    (patients with restricted intake of calcium or vitamin D may be more sensitive to medications that affect calcium homeostasis ^{01})

» Renal function impairment when serum creatinine is 2.5 to 4.9 mg per dL^{10}    (excretion of etidronate may be reduced ^{01}; reduction of dose may be necessary; in addition, renal function impairment may be exacerbated by etidronate infusion ^{10})

Sensitivity to etidronate

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

For Paget's disease and hypercalcemia
Renal function determinations, especially glomerular filtration rate (GFR) and/or blood urea nitrogen (BUN)^{10}    (recommended at periodic intervals during therapy; reduction in dosage in patients with impairment of renal function [GFR] should be considered and such patients closely monitored ^{09}; occasional mild to moderate abnormalities in renal function [increases of serum creatinine >0.5 mg per dL and elevated BUN] may occur when etidronate infusion is given to patients with hypercalcemia; these increases are reversible or may remain stable without worsening after completion of the course of infusion ^{10})

For Paget's disease only
Pain relief, assessment of    (pain may be an indication of Paget's disease activity; however, in elderly patients, biochemical indices, periodically monitored during therapy, are more valuable ^{03})

» Serum alkaline phosphatase concentrations and
» Urine hydroxyproline concentrations    (determinations recommended every 3 to 6 months during therapy; decreases in urine hydroxyproline ^{14} result from decreased collagen resorption following reduced osteoclastic activity and reduced bone resorption; decreases in alkaline phosphatase result from a secondary reduction in osteoblastic activity; reduction in both parameters are an indication of improvement; ^{14} sustained decreases during drug-free period are evidence of remission; retreatment is started when biochemical indices re-elevate to 75% of pretreatment values or symptoms recur ^{03} ^{24})

Serum phosphate concentrations    (determinations recommended prior to and 4 weeks after initiation of therapy; at higher doses [10 mg or more per kg of body weight per day], a rise of greater than 0.5 mg per deciliter over pretreatment is normal and without clinical consequence and is probably related to an alteration in renal tubular reabsorption of phosphate [normal values return within 2 to 4 weeks after discontinuation of etidronate]; a rise of 0.5 mg per deciliter or greater at lower doses [5 mg or less per kg of body weight per day] is uncommon and may indicate above average bioavailability; if such a rise is seen at the lower dose, the serum alkaline phosphatase and urinary hydroxyproline values should be examined for evidence that the drug is reducing bone turnover as expected; if there are no significant declines in these values, etidronate dosage should be reduced or the medication discontinued to avoid possible reduced mineralization of osteoid with no accompanying clinical benefit ^{31})

For hypercalcemia only
Serum albumin concentrations and
Serum calcium concentrations    (determinations recommended periodically during therapy; since serum proteins, especially albumin, may influence the ratio of free and bound calcium, corrected serum calcium values should be calculated by using an established algorithm; albumin-corrected serum calcium determinations may be useful when the signs and symptoms of hypercalcemia are inconsistent with unadjusted calcium values ^{10})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Bone pain or tenderness, increased, continuing, or recurrent —in patients with Paget's disease
Note: Usually occurs over the site of pagetic lesions, but sometimes occurs at previously asymptomatic sites, beginning within 4 to 6 weeks of initiation of therapy; more common with doses of 5 mg per kg of body weight (mg/kg) or greater for more than six months ^{15}. Pain may persist in some patients, even with continued therapy; usually subsides days to months after etidronate is discontinued.

Incidence less frequent

Osteomalacia ^{22}(bone fractures, especially of the femur)
Note: Usually occur in patients taking doses higher than 20 mg/kg or continuous administration of etidronate for longer than 6 months. ^{01} ^{20} Microfractures may be due to decreased strength of active pagetic bone or may be caused by a mineralization defect accompanying etidronate therapy.

Incidence rare

Allergic reaction, specifically ^{32}

angioedema (swelling of the extremities, face, lips, tongue, glottis, and/or larynx)

skin rash or itching

urticaria (hives)

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
—at higher doses
Diarrhea

nausea ^{22}

Incidence less frequent
—with parenteral dosage form
Loss of taste or metallic or altered taste ^{02}^{10}

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Etidronate (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to etidronate

Use in children—Children given adult dosages for nearly a year or more were reported to have signs of a rachitic syndrome that were reversible upon discontinuation of etidronate

Use in the elderly—Elderly patients may be more prone to overhydration when treated with parenteral etidronate in conjunction with hydration therapy
Other medications, especially antacids or mineral supplements
Other medical problems, especially renal function impairment, bone fractures, cardiac failure, or enterocolitis

Proper use of this medication
» Taking with water ^{21} on an empty stomach, at least 2 hours before or after food (upon arising, ^{21} midmorning, or at bedtime)

» Compliance with therapy; not taking more or less medication or for longer period of time than prescribed

Checking with physician before discontinuing medication; may require 1 to 3 months for symptomatic improvement ^{01}

» Maintaining a well-balanced diet with adequate intake of calcium and vitamin D; not taking within 2 hours of milk or milk products, antacids, mineral supplements, or other medicines high in calcium, magnesium, iron, or aluminum

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress even if between treatments

Checking with physician if nausea or diarrhea occurs and continues; dosage adjustment may be necessary

» Checking with physician if bone pain appears or worsens during treatment ^{17}

Side/adverse effects
Signs of potential side effects, especially increased or continuing bone pain, fractures, or allergic reaction

General Dosing Information
See also Patient monitoring.
For Paget's disease
Symptomatic improvement as evidence of ^{09} therapeutic response may not be seen for 1 to 3 months; dosage should not be prematurely increased or discontinued during that time.

Although etidronate is usually taken as a single dose, divided doses may be preferred if diarrhea or nausea occurs. ^{32}

In patients with Paget's disease, retreatment should be initiated only after a medication-free period of at least 3 months and only if there is evidence of active disease or if the biochemical indices have become re-elevated to 75% of pretreatment values or symptoms recur. ^{24} ^{32}

Analgesics may be required at any time if patient experiences bone pain. ^{23}

In many patients with Paget's disease, the disease process may be suppressed for a year or more after discontinuing therapy. ^{01}

Etidronate therapy in patients with total hip replacement does not promote loosening of the prosthesis or impede trochanteric reattachment. ^{32}

The dosage of etidronate should be reduced when there is a decrease in the glomerular filtration rate ^{25} ^{31}

For hypercalcemia
Retreatment with parenteral etidronate for more than 3 days and the safety and effectiveness of more than 2 courses of therapy have not been studied. ^{10}

The daily dose must be diluted in at least 250 mL of normal saline solution or 5% dextrose injection ^{16}. More of the diluent may be used, if convenient. ^{10} The diluted dose should be administered over a period of at least 2 hours. ^{14}

Limited clinical studies suggest that ^{14} oral administration of etidronate in some patients may be started on the day following the last dose of parenteral therapy. If serum calcium levels remain normal, treatment may be extended for up to 90 days. Normocalcemia may be defined as serum calcium concentrations usually within 8.5 to 10.5 mg per dL. ^{10}

Diet/Nutrition
Etidronate should be taken with water ^{21} on an empty stomach, at least 2 hours before or after food (e.g., upon arising, midmorning, or at bedtime) ^{21} for maximum absorption.

A well-balanced diet with adequate intake of calcium and vitamin D should be maintained. ^{31}

Foods containing large amounts of calcium, such as milk or other dairy products, mineral supplements, or other medicines high in calcium, magnesium, iron, or aluminum, may prevent absorption of etidronate and should not be taken within 2 hours of etidronate. ^{31}

Oral Dosage Forms

ETIDRONATE DISODIUM TABLETS USP

Usual adult dose
Paget's disease of bone
Oral, initially 5 mg per kg of body weight a day, usually as a single dose, for a period of time not to exceed six months; or 6 to 10 mg per kg of body weight a day, for a period of time not to exceed six months; or 11 to 20 mg per kg of body weight a day, for no longer than three months ^{20}.

Note: Doses above 5 ^{15} ^{17} mg per kg of body weight are recommended only when lower doses are ineffective or ^{09} there is an overriding requirement for suppression of increased bone turnover or when a more prompt reduction of elevated cardiac output is required. ^{31}
The retreatment dose after a drug-free period remains the same as the initial dose for most patients. ^{31}

Heterotopic ossification
Patients with total hip replacement: Oral, 20 mg per kg of body weight a day for one month prior to and for three months after surgery.
Patients with spinal cord injury: Oral, initially 20 mg per kg of body weight a day for two weeks, beginning as soon as medically feasible after injury and preferably before evidence of heterotopic ossification, the dosage then being decreased to 10 mg per kg of body weight a day for an additional ten weeks.

Hypercalcemia
Maintenance: Oral, 20 mg per kg of body weight a day for thirty days, up to a maximum of ninety days. ^{10} ^{32}

Usual adult prescribing limits
20 mg per kg of body weight a day. ^{31}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—

200 mg (Rx) [Didronel]

400 mg (Rx) [Didronel (scored)]

Canada—

200 mg (Rx) [Didronel]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take on an empty stomach.
   • Do not take with milk or antacids.

Parenteral Dosage Forms

ETIDRONATE DISODIUM INJECTION

Note: Etidronate disodium injection is not commercially available in Canada.

Usual adult dose
Hypercalcemia
Intravenous infusion, initially 7.5 mg per kg of body weight per day, administered over a period of at least two hours, for three consecutive days. ^{32}

Note: Some patients may be treated for up to seven days, but the risk of hypocalcemia is increased after three days. ^{32}
The retreatment dose after a seven-day drug-free interval remains the same as the initial dose for most patients. ^{32}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—

50 mg per mL (Rx) [Didronel]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
Dilute the daily dose in at least 250 mL of 0.9% sodium chloride injection or 5% dextrose injection ^{16}.

Stability:
Diluted solution may be stored at controlled room temperature for at least 48 hours without loss of drug. ^{10}

Revised: 08/05/1997

References

Didronel package insert (Norwich Eaton—US), Rev 1/83.

Jones BB, McCloskey EV, Kanis JA. Transient taste-loss during treatment with etidronate.Lancet 1987 Sep 12: 637.

Questions and anwers about Didronel therapy for symptomatic Paget's disease of bone. Procter & Gamble; 1979.

Krane SM. Etidronate disodium in the treatment of Paget's disease of the bone. Ann Intern Med 1982; 96: 619-25.

Mugglestone CJ. Etidronate and risk of fractures. Lancet 1986 Jun 15: 1393.

Khairi MRA, Johnston CC. Treatment of Paget's disease of the bone (osteitis deformans) with sodium etidronate (EHDP). Clin Ortho Rel Res 1977; 127: 94-105.