Etidronate

Etidronate is an Bisphosphonate Derivative belonging to pharmacology class of Diphosphonate.

Etidronate can be used in the treatment of Heterotopic ossification and Paget disease. Etidronate is used for preventing fractures caused by osteoporosis in postmenopausal women.

Etidronate is Variable and dose dependent (approx 1-6%). Reduced absorption w/ food and almost exclusively distributed into bone (approx 50% of absorbed amount) and get excreted Via urine, approx 50%. Elimination half-life: 1-6 hr.

Etidronate is available in the form of Tablets.

Etidronate disodium decreases bone resorption by inhibiting the growth and dissolution of hydroxyapatite crystals in bone and may also directly impair osteoclast activity.

Etidronate can be used in the treatment of Heterotopic ossification and Paget disease. Etidronate is used for preventing fractures caused by osteoporosis in postmenopausal women.

Etidronate decreases bone resorption by inhibiting osteocytic osteolysis; decreases mineral release and matrix or collagen breakdown in bone.

Etidronate is approved for use in the following clinical indications

Heterotopic ossification: Prevention and treatment of heterotopic ossification due to spinal cord injury or after total hip replacement

Paget disease: Symptomatic treatment of Paget disease of bone

Although not approved there have been certain off labelled uses documented for Etidronate which includes:-

Etidronate is used for preventing fractures caused by osteoporosis in postmenopausal women.

Paget disease: Oral:

Initial: 5 mg/kg/day (not to exceed 6 months) is recommended as initial therapy; if higher doses are needed, may give 5 to 10 mg/kg/day (not to exceed 6 months) or 11 to 20 mg/kg/day (not to exceed 3 months). Doses >10 mg/kg/day should be used only when lower doses are ineffective or there is a need to suppress rapid bone turnover (ie, potential for irreversible neurologic damage) or reduce elevated cardiac output. Doses >20 mg/kg/day are not recommended.

Re-treatment: Initiate only after etidronate-free period ≥90 days. Monitor patients every 3 to 6 months. Re-treatment regimens are the same as for initial treatment. In cases where the original dose is not adequate, consider increasing the dose within the recommended guidelines.

Heterotopic ossification: Oral:

Caused by spinal cord injury: 20 mg/kg/day for 2 weeks, then 10 mg/kg/day for 10 weeks; total treatment period: 12 weeks

Complicating total hip replacement: 20 mg/kg/day for 1 month preoperatively then 20 mg/kg/day for 3 months postoperatively; total treatment period is 4 months

Tablets

200 mg, 400 mg

Tablets

Dose Adjustment in Pediatric Patient:

Heterotopic ossification, traumatic brain injury: Limited data available: Children and Adolescents: Oral: Initial: 20 mg/kg/dose once daily for 2 to 4 weeks, then decrease to 10 mg/kg/dose once daily for 12 weeks to 1 year.

Ensure adequate calcium and vitamin D intake; women and men >50 years of age should consume 1,200 to 1,500 mg/day of elemental calcium and 800 to 1,000 units/day of vitamin D. Tablet should be taken with water or fruit juice on an empty stomach; avoid administering foods/supplements with calcium, iron, or magnesium within 2 hours of drug. Do not take with mineral water or with other beverages.

Etidronate may be contraindicated in the following conditions:-

Hypersensitivity to bisphosphonates or any component of the formulation; overt osteomalacia; patients with abnormalities of the esophagus (eg, stricture, achalasia) which delay esophageal emptying.

Concerns related to adverse effects:

• Bone/joint/muscle pain: Infrequently, severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.

• Fracture risk: Do not exceed recommended dose or use continuously for >6 months in patients with Paget's disease; risk of osteomalacia or fractures may be increased. Long bones with predominantly lytic lesions may be prone to fracture, particularly in patients unresponsive to treatment.

• GI mucosa irritation: May cause irritation to upper GI mucosa. Esophagitis, dysphagia, esophageal ulcers, esophageal erosions, and esophageal stricture (rare) have been reported with oral bisphosphonates; risk increases in patients unable to comply with dosing instructions. Use with caution in patients with dysphagia, esophageal disease, gastritis, duodenitis, or ulcers (may worsen underlying condition). Discontinue use if new or worsening symptoms develop.

• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates; this has been observed primarily following dental procedures such as tooth extractions and in cancer patients receiving IV bisphosphonates, but has also occurred in patients with postmenopausal osteoporosis and other diagnoses receiving oral bisphosphonates. Risk factors for MRONJ include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery), cancer diagnosis, concomitant chemotherapy, radiotherapy, or corticosteroids; anemia, coagulopathy, infection, ill-fitting dentures, or preexisting dental disease. According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonate and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy. The manufacturer’s labeling states that discontinuing bisphosphonates in patients requiring invasive dental procedures may reduce the risk of ONJ and clinical judgment should guide the decision. However, the AAOMS suggests there is currently no evidence that interrupting oral bisphosphonate therapy alters the risk of ONJ following tooth extraction, and that in patients receiving oral bisphosphonates for <4 years who have no clinical risk factors, no alternations or delay in any procedure common to oral/maxillofacial surgeons, periodontists, and other dental providers is necessary (special considerations apply to patients receiving dental implants). Conversely, in patients receiving oral bisphosphonates for >4 years or in patients receiving oral bisphosphonates for <4 years who have also taken corticosteroids or antiangiogenic medications concomitantly, the AAOMS recommends considering a 2-month drug free period prior to invasive dental procedures (recommendation based on a theoretical benefit). Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]). According to the manufacturer, discontinuation of the bisphosphonate therapy should be considered (based on risk/benefit evaluation) in patients who develop ONJ.

Disease-related concerns:

• Bariatric surgery: Altered absorption and ulceration risk: Avoid oral bisphosphates after bariatric surgery; inadequate oral absorption and potential anastomotic ulceration may occur. If therapy is indicated, IV administered bisphosphonates are recommended.

• Enterocolitis: Use with caution in patients with enterocolitis; diarrhea has been reported at high doses and therapy may need to be withheld.

• Renal impairment: Use with caution in patients with renal impairment.

There is no sufficient scientific evidence traceable regarding use and safety of Etidronate in concurrent use with alcohol.

It is not known if etidronate is present in breast milk.

Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue the drug, taking considering the importance of treatment to the mother.

Pregnancy Category (FDA): C

In teratology and developmental toxicity studies conducted in rats and rabbits treated with dosages of up to 100 mg/kg (5 to 20 times the clinical dose), no adverse or teratogenic effects have been observed in the offspring. Etidronate disodium has been shown to cause skeletal abnormalities in rats when given at oral dose levels of 300 mg/kg (15 to 60 times the human dose). Other effects on the offspring (including decreased live births) are at dosages that cause significant toxicity in the parent generation and are 25 to 200 times the human dose. The skeletal effects are thought to be the result of the pharmacological effects of the drug on bone.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous vs. oral) on this risk has yet to be studied.

There are no adequate and well controlled studies in pregnant women. Etidronate disodium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Food and/or supplements decrease the absorption and bioavailability of the drug. Management: Administer tablet on an empty stomach with a full glass of plain water or fruit juice (6 to 8 oz) 2 hours before food. Avoid administering foods/supplements with calcium, iron, or magnesium within 2 hours of drug. Do not take with mineral water or other beverages.

The adverse reactions related to Etidronate can be categorized as

Common Adverse effects:

Agranulocytosis, alopecia, amnesia, angioedema, arthralgia, arthritis, bone fracture, confusion, depression, erythema multiforme, esophagitis, exacerbation of asthma, exacerbation of peptic ulcer, folliculitis, gastritis

Less Common Adverse effects:

Glossitis, glossopyrosis, hallucination, headache, hypersensitivity reaction, leg cramps, leukemia, leukopenia, maculopapular rash, osteomalacia

Rare Adverse effects:

The clinically relevant drug interactions of Etidronate is briefly summarized here

• May increase prothrombin time w/ warfarin.
• May enhance the adverse effects of deferasirox.
• Decreased serum concentration w/ antacids, multivitamins/minerals.
• Increased hypocalcaemic effect w/ aminoglycosides.
• Increased adverse/toxic effect w/ NSAIDs, systemic angiogenesis inhibitors.
• Diminished therapeutic effect w/ PPIs.

The most common side effects of Etidronate includes: Agranulocytosis, alopecia, amnesia, angioedema, arthralgia, arthritis, bone fracture, confusion, depression, erythema multiforme, esophagitis, exacerbation of asthma, exacerbation of peptic ulcer, folliculitis, gastritis.

Pregnancy Category (FDA): C

• In teratology and developmental toxicity studies conducted in rats and rabbits treated with dosages of up to 100 mg/kg (5 to 20 times the clinical dose), no adverse or teratogenic effects have been observed in the offspring. Etidronate disodium has been shown to cause skeletal abnormalities in rats when given at oral dose levels of 300 mg/kg (15 to 60 times the human dose). Other effects on the offspring (including decreased live births) are at dosages that cause significant toxicity in the parent generation and are 25 to 200 times the human dose. The skeletal effects are thought to be the result of the pharmacological effects of the drug on bone.
• Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous vs. oral) on this risk has not been studied.
• There are no adequate and well controlled studies in pregnant women. Etidronate disodium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

There is no FDA guidance on use of Etidronate during labor and delivery.

Nursing Mothers

• It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when etidronate disodium is administered to a nursing woman.

Pediatric Use

• Safety and effectiveness in pediatric patients have not been established. Pediatric patients have been treated with etidronate disodium, at doses recommended for adults, to prevent heterotopic ossifications or soft tissue calcifications. A rachitic syndrome has been reported infrequently at doses of 10 mg/kg/day and more for prolonged periods approaching or exceeding a year. The epiphyseal radiologic changes associated with retarded mineralization of new osteoid and cartilage, and occasional symptoms reported, have been reversible when medication is discontinued.

Geriatric Use

• Clinical studies of etidronate disodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. As stated in PRECAUTIONS, etidronate disodium dosage should be reduced when reductions in glomerular filtration rates are present. In addition, patients with renal impairment should be closely monitored.

Gender

There is no FDA guidance on the use of Etidronate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Etidronate with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Etidronate in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Etidronate in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Etidronate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Etidronate in patients who are immunocompromised.

Symptoms: Hypocalcemia, vomiting, paranesthesia of the fingers, diarrhea, electrolyte imbalance.

Management: Employ gastric lavage for acute overdosage. Parenteral admin of Ca salt (e.g. IV Ca gluconate) may be given to relieve signs and symptoms of hypocalcemia.

• Pharmacodynamics:

Etidronate disodium acts primarily on bone. It can inhibit the formation, growth, and dissolution of hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required to inhibit crystal growth. Both effects increase as the dose increases.

• Pharmacokinetics:

Absorption: Variable and dose dependent (approx 1-6%). Reduced absorption w/ food.

Distribution: Almost exclusively distributed into bone (approx 50% of absorbed amount).

Metabolism: Not metabolized.

Excretion: Via urine, approx 50%. Elimination half-life: 1-6 hr.

1. https://www.uptodate.com/contents/ Etidronate -drug-information?search= Etidronate &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Etidronate _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Etidronate ?type=full&mtype=generic#mechanism-of-action