ATC Class:M05BA01
VA Class:HS900
Etidronate disodium is a synthetic bisphosphonate analog of pyrophosphate, a naturally occurring inhibitor of bone metabolism.
Etidronate disodium is used orally in the treatment of moderate to severe symptomatic Paget disease of bone (osteitis deformans) 131, 132, 141, 142, 143, 144, 145, 146 and in the prevention and treatment of heterotopic ossification following total hip arthroplasty or spinal cord injury. The drug also has been used in the prevention and treatment of glucocorticoid-induced osteoporosis†.131, 132, 141, 142, 143, 144, 145, 146 Etidronate has been used IV (an IV preparation is no longer commercially available in the US) in conjunction with adequate hydration for the treatment of hypercalcemia associated with malignant neoplasms.100, 101, 102, 105, 110, 111, 112, 127, 152
Etidronate disodium is used orally in the treatment of moderate to severe symptomatic Paget disease of bone (osteitis deformans). In most patients with Paget disease, only small areas of bone are involved and patients are usually asymptomatic; mild symptoms in these patients can usually be controlled with analgesics. Treatment with etidronate disodium should be considered in patients with moderate to severe pain or in those with neural compression or increased cardiac output resulting from Paget disease of bone. There is no evidence that prophylactic use of etidronate disodium will benefit asymptomatic patients; however, prophylactic treatment may be considered in patients with extensive involvement of the skull or spinal column and the possibility of irreversible neurologic damage or in those with extensive involvement threatening major joints or weight-bearing bones.
The efficacy of etidronate disodium has been demonstrated mainly in patients with symptomatic Paget disease characterized by multiple bone involvement (polyostotic) and elevated concentrations of serum alkaline phosphatase and urinary hydroxyproline. In these patients, treatment with the drug has decreased elevated serum alkaline phosphatase concentrations and urinary hydroxyproline excretion and, in some patients, relieved bone pain and/or increased mobility. Reductions in increased cardiac output and skin temperature associated with Paget disease also occur in some patients. Reduced urinary excretion of hydroxyproline is often the first sign of therapeutic response and occurs after 1-3 months of therapy. Reductions in serum alkaline phosphatase and urinary hydroxyproline concentrations reach a plateau in about 6 months and usually further improvements in the biochemical abnormalities associated with Paget disease do not occur with more prolonged therapy. Urinary hydroxyproline and serum alkaline phosphatase concentrations may slowly increase toward pretreatment values when etidronate disodium therapy is discontinued. In many patients, the disease process will be suppressed for a period of at least 1 year (the upper limit of this period has not been established) following discontinuance of therapy. In patients whose disease is most likely to relapse, relapse generally tends to occur within about 3-24 months. The time to relapse probably depends on the severity of biochemical abnormalities prior to therapy; patients having higher pretreatment urinary hydroxyproline and serum alkaline phosphatase concentrations usually relapse earlier. Many patients who receive a second course (and subsequent additional courses) of etidronate disodium therapy after relapse of biochemical and/or clinical symptoms respond about as well as during the first treatment period, although higher dosages may be necessary. Some patients develop resistance to the drug with subsequent courses of therapy, even at the maximum recommended dosage. Some data indicate that resistance to etidronate disodium is most likely to develop in patients who require more than one course of therapy with the drug per year, whose initial serum alkaline phosphatase concentration exceeds 6 times normal, and whose initial urinary excretion of hydroxyproline exceeds 10 times normal.107 It is not known if control of the biochemical abnormalities of Paget disease will prevent complications such as deafness, deformities, fractures, neurologic manifestations, sarcoma, or heart failure; symptoms resulting from bowing of the tibia or femur, destruction of a joint, or nerve compression may not be reversed. Although diminished hearing loss reportedly occurred in a few patients with Paget disease of the skull during etidronate disodium therapy, there has been no objective evidence of improved hearing attributable to treatment with the drug.
In a comparative clinical trial in men and women with moderate to severe Paget disease of bone (serum alkaline phosphatase concentrations at least twice the upper limit of normal) receiving either oral etidronate disodium (400 mg daily for 6 months) or risedronate sodium (30 mg daily for 2 months), normalization of serum alkaline phosphatase concentrations at 6 months of therapy occurred in 77% of patients receiving risedronate and 11% of those receiving etidronate.129 Normalization of serum alkaline phosphatase concentrations occurred more rapidly with risedronate than with etidronate therapy.129 Suppression of the disease process (i.e., serum alkaline concentrations remaining within the normal range) was still apparent at 18 months (16 or 12 months after discontinuance of risedronate or etidronate, respectively) in 53 versus 14% of patients who had received risedronate or etidronate, respectively. 129 The efficacy of etidronate or risedronate reportedly was not affected by the severity of Paget disease.128
The relative effectiveness of calcitonin and etidronate disodium in the treatment of Paget disease has not been determined, and it is not known if etidronate disodium is effective in patients refractory to calcitonin. Unlike calcitonin, etidronate disodium can bring biochemical abnormalities to normal in extremely severe cases. Etidronate disodium produces less severe adverse effects than plicamycin (no longer commercially available in the US) and, unlike either calcitonin or plicamycin, etidronate disodium can be given orally. There is limited evidence suggesting that sequential therapy with etidronate disodium and calcitonin produces greater therapeutic benefit when etidronate disodium is administered before calcitonin rather than vice versa.108 In a limited number of patients, etidronate disodium has been used effectively in conjunction with calcitonin human in the treatment of Paget disease.
Etidronate disodium is used in the prevention and treatment of heterotopic ossification (myositis ossificans, ectopic calcification, periarticular ossification, or paraosteoarthropathy) following total hip arthroplasty or resulting from spinal cord injury. Heterotopic ossification, which is characterized by metaplastic osteogenesis, may be idiopathic (e.g., myositis ossificans progressiva); may follow surgical, occupational, or sports trauma; or may be non-traumatic (e.g., associated with CNS infections, peripheral neuropathy, tetanus, biliary cirrhosis, Peyronie disease, or benign or malignant neoplasms). Heterotopic ossification occurs in about 50% of patients following total hip arthroplasty and in about 40% of patients following spinal cord injury; about one-third and one-half of these cases, respectively, are clinically important. The efficacy of etidronate disodium in the treatment of idiopathic heterotopic ossification or heterotopic ossification associated with other conditions has not been established.
In the treatment of heterotopic ossification, etidronate disodium decreases the incidence, severity, and progression of heterotopic bone lesions; however, there is no evidence that therapy with etidronate disodium affects mature heterotopic bone. The effect of etidronate disodium has been shown to persist for at least 9 months after therapy with the drug has been discontinued. Etidronate disodium has not caused loosening of the prosthesis nor interfered with reattachment of the trochanter when used in patients following total hip arthroplasty. Etidronate disodium has not inhibited fracture healing or stabilization of the spine in patients with spinal cord injury.
Hypercalcemia Associated with Malignancy
Etidronate disodium has been used IV (an IV preparation no longer is available in the US) in conjunction with achievement and maintenance of adequate hydration for the treatment of hypercalcemia associated with malignant neoplasms that is not adequately managed by dietary modification and/or oral hydration.100, 101, 102, 105, 110, 111, 112 Data are extremely limited but suggest that oral etidronate disodium has limited potential value for the acute treatment of malignancy-associated hypercalcemia†.113, 114
Glucocorticoid-induced Osteoporosis
Bisphosphonates, including etidronate, have been used effectively for the prevention and treatment of glucocorticoid-induced osteoporosis†.131, 132, 133, 134, 135, 136, 137, 141, 142, 143, 144, 145, 146, 166, 622 For additional information on the use of bisphosphonates for prevention and treatment of glucocorticoid-induced osteoporosis, see Uses: Glucocorticoid-induced Osteoporosis, in Alendronate 92:24.
Etidronate disodium has been used orally in severely disabled patients with calcifications caused by myositis ossificans progressiva† or calcinosis universalis†; the drug may be at least partially effective in the management of these conditions, but further investigation is required. The drug appears to be ineffective in the treatment of calcinosis resulting from dermatomyositis and scleroderma. Oral etidronate disodium, alone or in combination with calcitonin, has reportedly been effective in a few patients for the treatment of hypercalcemia caused by immobilization†.117, 118, 119
In a limited number of patients with primary hyperparathyroidism, oral etidronate disodium has been used to prevent parathyroid hormone-induced bone resorption†. Although the drug is generally considered ineffective for the treatment of hypercalcemia of primary hyperparathyroidism,100, 114, 120 some data indicate that it may occasionally be of value in an individual patient.114, 121
Etidronate disodium is administered orally as a single daily dose; however, dosage of the drug may be divided if adverse GI effects occur during therapy.125 To facilitate absorption, etidronate should be taken with a full glass (180-240 mL) of plain water.125 Patients should be instructed to avoid lying down following oral administration of etidronate.125 Since absorption of etidronate disodium may be reduced by food, especially food rich in calcium, eating should be avoided for 2 hours before and after the drug is administered. Vitamins with mineral supplements or antacids that contain metals such as calcium, iron, magnesium, or aluminum may also affect absorption of etidronate disodium and should be avoided within 2 hours of etidronate disodium administration.125
For the treatment of Paget disease of bone, initial adult dosage regimens of oral etidronate disodium are 5-10 mg/kg daily for no longer than 6 months or 11-20 mg/kg daily for no longer than 3 months. The recommended initial adult oral dosage is 5 mg/kg daily for no longer than 6 months.
In patients with Paget disease of bone, onset of therapeutic response of etidronate disodium may be delayed, and therapeutic effects may persist for months after the drug has been withdrawn. Premature increases in dosage should be avoided, since increased dosage may cause mineralization defects in normal or pagetic bone. In patients who require immediate suppression of excessive bone remodeling or reduction of elevated cardiac output associated with Paget disease or in whom lower dosages are ineffective, oral etidronate disodium dosages exceeding 10 mg/kg daily may be used; treatment with these dosages should be used cautiously and should be continued for no longer than 3 months.125 Oral dosages of etidronate disodium exceeding 20 mg/kg daily are not recommended. The effect of the drug should be monitored by periodic determinations of serum concentrations of alkaline phosphatase and urinary hydroxyproline.
In patients with Paget disease, courses of etidronate disodium therapy should be separated by drug-free periods of at least 3 months. Although some patients may go drug-free for extended periods, patients should be monitored for recurrence of disease every 3-6 months. Retreatment should be considered if there is evidence of recurrence of the disease process and urinary hydroxyproline or serum alkaline phosphatase concentrations become twice the upper limit of normal (in patients whose biochemical indicators became normal during treatment) or approach 75% of pretreatment concentrations. Dosage requirements of etidronate disodium for retreatment of Paget disease are usually the same as those required for initial treatment, but increased dosage of the drug within the recommended range should be considered if the original dosage produces an inadequate response.
In one study in patients with Paget disease, etidronate disodium 7.5 mg/kg daily was given orally in 3 divided doses concomitantly with 500 mcg of synthetic human calcitonin daily by subcutaneous injection for 1 year.
For the prevention and treatment of heterotopic ossification resulting from spinal cord injury, therapy with oral etidronate disodium should be initiated as soon as it is feasible following the injury and preferably before any radiographic evidence of heterotopic ossification. The initial adult dosage of etidronate disodium is 20 mg/kg daily for 2 weeks followed by 10 mg/kg daily for an additional 10 weeks. The total treatment period is 12 weeks. Retreatment has not been studied in these patients, since heterotopic ossification occurs most frequently in the period immediately after the injury.
For the prevention and treatment of heterotopic ossification in patients following total hip arthroplasty, the usual initial adult dosage of oral etidronate disodium is 20 mg/kg daily administered preoperatively for 1 month and postoperatively for an additional 3 months. The total treatment period is 4 months. Retreatment with etidronate disodium has not been studied to date in patients with total hip arthroplasty.
Glucocorticoid-induced Osteoporosis
For the prevention and/or treatment of glucocorticoid-induced osteoporosis†, etidronate disodium has been administered orally on an intermittent basis in a cyclic regimen (e.g., 400 mg daily for 2 weeks every 3 months), usually in conjunction with calcium (e.g., 500 mg daily) and vitamin D supplementation during the remaining 10-11 weeks of each cycle or on a continuous basis.141, 142, 143, 144, 145, 146
For treatment of myositis ossificans progressiva† or calcinosis universalis†, etidronate disodium has been used orally at dosages of 10-20 mg/kg daily. For prevention of parathyroid hormone-induced bone resorption†, the drug has been used orally at dosages of 5-20 mg/kg daily.
Dosage in Renal and Hepatic Impairment
Dosage of etidronate should be reduced in patients with reduced glomerular filtration.125 Such patients should be closely monitored.125 (See Cautions: Precautions and Contraindications.) In addition, since geriatric individuals are more likely to have decreased renal function, care should be taken in dosage selection for such patients.125
Etidronate disodium is usually well tolerated following oral administration. Adverse effects are generally dose related and rarely occur when the drug is given at an oral dosage of 5 mg/kg daily.
Since severe adverse esophageal effects including esophagitis, esophageal ulcers, and/or erosions (occasionally with bleeding and rarely followed by esophageal stricture or perforation) have been reported in patients receiving oral bisphosphonates, clinicians should be alert to any sign or symptom associated with such adverse effects.125 Patients should be instructed to discontinue etidronate and contact a clinician if dysphagia, odynophagia, retrosternal pain, or new or worsening heartburn occurs.125 Since the incidence of severe adverse esophageal effects is greater in patients who do not drink a full (180-240 mL) glass of water when taking the drug and in those who do not avoid lying down for at least 30 minutes following administration of etidronate or who continue to take the drug after experiencing symptoms suggestive of esophageal irritation, patients should be instructed carefully about proper administration of the drug and should be given a copy of the patient instructions provided by the manufacturer.125 Etidronate should be used with caution in patients with active upper GI disease (e.g., Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, ulcers) or a history of such problems.125
Occasionally, diarrhea, loose stools, nausea, GI upset, abdominal discomfort, vomiting, and occult blood in stools have been reported in patients receiving oral etidronate disodium, especially at dosages of 20 mg/kg daily. Diarrhea is often relieved by giving the drug in divided doses. One patient who received 20 mg/kg of etidronate disodium daily for 3 months developed pseudomembranous colitis that was believed to be due to the drug. Exacerbation of existing peptic ulcer disease has been reported during worldwide postmarketing experience in a few patients receiving oral etidronate; perforation of peptic ulcer also has occurred in at least one patient.125 During postmarketing experience in clinical trials in patients with osteoporosis†, gastritis occurred more frequently with oral etidronate therapy than with placebo.125 Gastric or duodenal ulcers, including some that were severe and with complications, have been reported with oral bisphosphonates during postmarketing experience, although no increased risk was observed in controlled clinical trials.125 Although a causal relationship to the drug was not definitely established, gastric ulcer occurred in a patient who received 20 mg/kg of etidronate disodium daily for 18 months.
Although data are conflicting, there is some evidence suggesting a possible association between use of oral bisphosphonates and an increased risk of esophageal cancer.156, 160 During the period of postmarketing surveillance from October 1995 (initial marketing of alendronate) through mid-May 2008, FDA received reports of esophageal cancer in 23 patients in the US receiving alendronate (as the suspect drug in 21 cases and the concomitant drug in 2 cases); 8 deaths were reported.156 An additional 31 cases of esophageal cancer were reported at the time in patients in Europe and Japan who had received an oral bisphosphonate, including alendronate, risedronate, ibandronate, and etidronate.156 (See Upper GI Effects under Cautions: Warnings/Precautions, in Alendronate 92:24.) In a large case-control study in a cohort of patients from the UK General Practice Research Database, risk of esophageal cancer was increased by 30% in patients who had at least one prescription issued for an oral bisphosphonate (alendronate, etidronate, or risedronate) compared with those not receiving such prescriptions; the risk was approximately doubled among patients who had 10 or more prescriptions issued for an oral bisphosphonate or who had an estimated duration of bisphosphonate use (calculated as the time between the first and last prescription issued during the observation period) of more than 3 years.160, 161 However, another retrospective cohort study that used the same database found no evidence of an increased risk of esophageal cancer in patients receiving oral bisphosphonates.160, 162 Other observational studies, including a study in patients receiving long-term alendronate therapy and a cohort study of Danish patients with fractures, have shown either no risk or a reduced risk of esophageal cancer following use of oral bisphosphonates.160, 163, 164, 165 Because of conflicting findings and limitations of currently available data,161, 162, 163 additional study is needed to determine the association, if any, between oral bisphosphonate use and esophageal cancer.160 FDA states that the benefits of oral bisphosphonates in reducing the risk of serious fractures continue to outweigh their potential risks in patients with osteoporosis and that it is important to consider that esophageal cancer is rare, especially in women.160, 161 FDA also states that there is insufficient information at this time to recommend routine endoscopic screening in asymptomatic patients receiving oral bisphosphonates.160 Avoidance of oral bisphosphonates in patients with Barrett's esophagus, a known precursor to esophageal adenocarcinoma, has been recommended.156
Metallic or altered taste and loss of taste have occurred during and/or shortly after IV administration of etidronate disodium (an IV preparation is no longer commercially available in the US).100, 101, 102 The effects on taste persisted throughout the infusion of the drug and in some patients throughout the course of treatment102 but usually disappeared within hours100, 101 and disappeared rapidly following discontinuance of therapy.102 Esophagitis or glossitis has been reported during worldwide postmarketing experience with oral etidronate therapy.125
Acute renal failure has been reported rarely with IV etidronate therapy (an IV preparation is no longer commercially available in the US); concomitant use of nonsteroidal anti-inflammatory agents or diuretics may have contributed to renal failure in such patients.100 IV administration of the drug at doses and possibly at rates exceeding those recommended has been reported to be associated with renal insufficiency.100, 101, 123 In animals, IV administration at doses or rates exceeding those recommended produced proximal renal tubule damage.100, 101
Increased serum phosphate concentrations may occur in patients receiving etidronate disodium, especially with oral dosages of 10-20 mg/kg daily; hyperphosphatemia appears to result from drug-related increases in tubular reabsorption of phosphate.125 Adverse effects of etidronate disodium-induced hyperphosphatemia have not been noted, and hyperphosphatemia is not an indication to stop therapy. Serum phosphorus concentrations of 7 mg/dL and higher have been reported in patients receiving oral etidronate disodium. Serum phosphate concentrations usually return to pretreatment values 2-4 weeks after the drug is withdrawn.125
Clinically important changes in concentrations of serum parathyroid hormone or serum calcium have not been reported in patients receiving oral etidronate disodium.
Dermatologic and Sensitivity Reactions
Alopecia has been reported during worldwide postmarketing experience in patients receiving oral etidronate therapy.125
Hypersensitivity reactions including angioedema, follicular eruption, urticaria, macular or maculopapular rash, and/or pruritus have been reported rarely in patients receiving oral etidronate disodium therapy. Stevens-Johnson syndrome has been reported during worldwide postmarketing experience in at least one patient receiving oral etidronate.125
Amnesia, confusion, depression, hallucination, or paresthesia has been reported during worldwide postmarketing experience with oral etidronate therapy.125 During postmarketing experience in clinical trials in patients with osteoporosis†, headache occurred more frequently with oral etidronate therapy than with placebo.125
Some patients treated for Paget disease with etidronate disodium experience recurrence or worsening of pain at pagetic lesions and develop pain at new sites; this effect is more common in patients receiving an oral dosage of 10 or 20 mg/kg daily than in those receiving 5 mg/kg daily. Bone biopsy in some of these patients who were receiving 20 mg/kg daily showed widened osteoid seams suggesting impaired mineralization of new osteoid. The pain may continue or even worsen as urine hydroxyproline and serum alkaline phosphatase concentrations reach normal. In some patients, the pain will resolve with continued drug therapy. In 2 patients with Paget disease receiving etidronate disodium, pain of preexisting osteoarthritis of the knees and hips worsened. A rickets-like syndrome has been reported in a few children receiving high doses of the drug for prolonged periods. Arthropathies, including arthralgia and arthritis, have been reported during worldwide postmarketing experience with oral etidronate therapy.125 During postmarketing experience in clinical trials in patients with osteoporosis†, leg cramps and arthralgia occurred more frequently with oral etidronate therapy than with placebo.125
Osteonecrosis and osteomyelitis of the jaw have been reported in patients, principally in those with cancer, who have received bisphosphonates.125, 147, 148, 149, 150, 151 Most instances of osteonecrosis of the jaw have been observed during IV bisphosphonate therapy, but some patients have experienced this adverse effect during oral bisphosphonate therapy, including with etidronate.125 (See Osteonecrosis of the Jaw under Cautions: Warnings/Precautions, in Zoledronic Acid 92:24.) Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and comorbid disorders (e.g., periodontal and/or other preexisting dental disease, anemia, coagulopathy, infection, ill-fitting dentures).125 Discontinuance of bisphosphonate treatment may reduce the risk for osteonecrosis of the jaw in patients requiring invasive dental procedures.125 Clinical judgment of the treating clinician and/or oral surgeon should guide the management of each patient based on individual benefit/risk assessment.125 Patients who develop osteonecrosis of the jaw while receiving bisphosphonate therapy should receive care by an oral surgeon.125 In these patients, extensive dental surgery to treat osteonecrosis of the jaw may exacerbate the condition.125 Discontinuance of bisphosphonate therapy should be considered based on assessment of benefits and risks in individual patients.125
Severe, occasionally incapacitating bone, joint, and/or muscle pain has been reported infrequently during postmarketing experience in patients receiving bisphosphonates, including etidronate.125, 148, 153, 154 The time to onset of symptoms varied from 1 day to years (mean onset about 3 months) after treatment initiation.125, 153 Musculoskeletal pain has improved following discontinuance of the drug in most patients; however, some patients have reported slow or incomplete resolution of such pain.125, 148, 153 In some patients, musculoskeletal pain recurred upon subsequent rechallenge with the same drug or another bisphosphonate.125, 154 (See Musculoskeletal Pain under Cautions: Warnings/Precautions, in Zoledronic Acid 92:24.)
Atypical femoral fractures involving the subtrochanteric region of the hip (i.e., below the lesser trochanter) and the diaphyseal region (or shaft) of the femur have been reported with long-term (i.e., at least 3-5 years) of bisphosphonate therapy.157, 158, 159 The magnitude of this risk with bisphosphonate therapy is unclear, although such fractures appear to be rare;157, 158, 159 in addition, causality has not been established since atypical fractures also have occurred in patients not receiving bisphosphonates.157, 158 Most cases of atypical femoral fractures with bisphosphonate therapy have been reported in individuals receiving treatment for osteoporosis.157 (See Atypical Fracture of the Femur under Cautions: Warnings/Precautions, in Zoledronic Acid 92:24.)
Agranulocytosis or pancytopenia has been reported rarely during worldwide postmarketing experience with oral etidronate; leukopenia that recurred upon rechallenge also has been reported.125
Exacerbation of asthma has been reported rarely during worldwide postmarketing experience with oral etidronate therapy.125
During worldwide postmarketing experience in clinical trials in patients with osteoporosis†, headache, gastritis, leg cramps, and arthralgia occurred more frequently with oral etidronate therapy than with placebo.125
Prolonged continuous treatment with oral etidronate disodium (chronic overdosage) has been reported to cause nephrotic syndrome and fractures.125
While data are conflicting, a possible increased risk of atrial fibrillation has been identified with use of bisphosphonates.155 (See Atrial Fibrillation under Cautions: Warnings/Precautions, in Zoledronic Acid 92:24.)
Precautions and Contraindications
Patients whose intake of calcium and vitamin D is restricted may be especially sensitive to the effects of etidronate disodium and should be observed closely while undergoing therapy. All patients receiving oral etidronate disodium should be advised to maintain an adequate intake of calcium and vitamin D while taking the drug. In some patients with enterocolitis, oral therapy with etidronate disodium has been withheld since diarrhea may occur, especially with high dosages.125
Etidronate disodium therapy, when given orally at dosages of 20 mg/kg daily for longer than 6 months, may increase the risk of fracture in some patients with Paget disease. The risk may be greater in those with extensive and severe Paget disease, a history of multiple fractures, and/or rapidly progressing disease. Long bones affected mainly by lytic lesions, particularly in patients whose disease is unresponsive to etidronate therapy, may be especially prone to fractures. Therefore, patients with lytic lesions should be monitored closely, both radiographically and biochemically, to permit timely termination of etidronate therapy in those whose disease is unresponsive. Some data suggest that focal osteomalacia may occur even at relatively low recommended dosages (5-8 mg/kg orally daily) and could contribute to the risk of fracture.124 In patients with Paget disease, etidronate disodium should be discontinued if fractures occur and withheld until fractures have healed. In patients with spinal cord injury, concomitant fractures are common but problems with fracture healing or stabilization of the spine have not been reported during therapy with the drug. Since the incidence of osteogenic sarcoma is increased in patients with Paget disease, lesions should be carefully evaluated to differentiate pagetic sites from osteogenic sarcoma.
Since etidronate disodium is excreted unchanged by the kidneys, the drug should be used with caution, if at all, in patients with impaired renal function.100, 125 When reductions in glomerular filtration rate are present in patients receiving etidronate disodium, dosage of the drug should be reduced.100, 125 Patients with impaired renal function who are receiving etidronate disodium should be carefully monitored.100, 125
Etidronate is contraindicated in patients with abnormalities of the esophagus that delay esophageal emptying, such as stricture or achalasia.125 The drug also is contraindicated in patients with known hypersensitivity to the drug and in those with clinically overt osteomalacia.125
Safety and efficacy of oral etidronate disodium in children have not been established. Etidronate disodium has been used in children for the prevention of heterotopic ossification or soft tissue calcification at weight-adjusted dosages recommended for adults. However, a rachitic syndrome has been reported infrequently in children receiving oral etidronate disodium dosages of 10 mg/kg daily for approximately 1 year or longer. Epiphyseal radiographic changes associated with retarded mineralization of new osteoid and cartilage and associated occasional symptoms were reversible following discontinuance of the drug in these children.
Clinical trials of etidronate did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults.125 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease in geriatric patients, dosage selection should be cautious in such patients.125 Since etidronate is excreted substantially by the kidneys, the risk of toxic reactions to the drug may be greater in patients with impaired renal function.125 In addition, since geriatric individuals are more likely to have decreased renal function, care should be taken in dosage selection for such patients.125
In long-term studies in rats, no evidence of carcinogenicity was observed with etidronate disodium.125 However, esophageal cancer has been reported in patients receiving etidronate and/or other bisphosphonates.156 (See Cautions: GI Effects.)
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits using oral etidronate disodium dosages up to 100 mg/kg (5-20 times the maximum human dosage) have not revealed evidence of harm to the fetus.125 At oral dosages 25-200 times the maximum human dosage, substantial toxicity to the parent generation and a decrease in live fetuses was observed in rats.125 Skeletal malformations attributed to the pharmacologic effect of the drug were the only malformations observed in rats at exaggerated dosages following parenteral administration and with an oral dose of 300 mg/kg (15-60 times the human clinical dose).125
Although no data are available on the fetal risk of bisphosphonates in humans, these drugs do cause fetal harm in animals.125 Data from animals suggest that uptake of bisphosphonates into fetal bone is greater than that into maternal bone.125 A theoretical risk to the fetus (e.g., skeletal and other abnormalities) exists if a woman becomes pregnant after completing a course of bisphosphonate therapy.125 The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (IV versus oral) on this risk has not been established.125
There are no adequate and controlled studies to date of oral etidronate disodium use in pregnant women, and the drug should be used during pregnancy if the potential benefit justifies the potential risk to the fetus.125
Reproduction studies in rats and rabbits using oral etidronate disodium dosages up to 100 mg/kg (5-20 times the maximum human dosage) have not revealed evidence of impaired fertility.125
Since it is not known if etidronate disodium is distributed into milk, the drug should be used with caution in nursing women.
Studies in animals have shown that etidronate disodium does not affect the antineoplastic activity of carmustine, cyclophosphamide, doxorubicin, or fluorouracil.100, 101, 103, 104
Increases in prothrombin time have been reported occasionally following addition of etidronate therapy in patients receiving warfarin.125In most cases, elevations in prothrombin time were variable and without clinically important sequelae.125 However, while the relevance and mechanism of any coagulation alterations are unclear, patients receiving warfarin should have their prothrombin time monitored when etidronate is added to therapy.125
There is limited clinical experience to date with acute overdosage of etidronate disodium.100, 125
Pathogenesis and Manifestation
Following a substantial oral overdosage, decreases in serum calcium concentration would be expected in some patients; signs and symptoms of hypocalcemia may also occur in some of these patients.125 Some patients may develop vomiting.125 Paresthesias of the fingers occurred in an 18-year old woman who was reportedly mildly hypocalcemic (serum calcium concentration of 7.52 mg/dL) following ingestion of an estimated single etidronate disodium dose of 4-6 g (67-100 mg/kg).125 Hypocalcemia resolved 6 hours after lavage and treatment with IV calcium gluconate.125 Marked diarrhea and electrolyte imbalance requiring treatment occurred in a 92-year old woman who accidentally received 1.6 g of etidronate disodium daily for 3.5 days.125
IV administration of etidronate disodium (an IV preparation is no longer commercially available in the US) at doses and possibly rates in excess of those recommended has been reported to be associated with renal insufficiency.100, 101, 123 In animals, IV administration at doses or rates exceeding those recommended produced transient hypocalcemia100, 101, 126 and proximal renal tubule damage.100, 101 Following rapid IV administration of etidronate disodium doses exceeding 27 mg/kg in animals, electrocardiographic (ECG) changes100, 101, 126 (including serious arrhythmias),126 bleeding problems,100, 101 and, in some cases, death occurred.126 The ECG changes and bleeding problems appear to be related to marked and/or rapid decreases in ionized calcium concentrations in blood and tissues which are probably caused by chelation of calcium by the large amounts of drug administered; these toxicities were shown to be reversible with IV administration of calcium gluconate.100, 101, 126
Following acute overdosage of oral etidronate disodium, gastric lavage may remove unabsorbed drug.125 Following overdosage with oral etidronate disodium, conventional measures for the treatment of hypocalcemia, including parenteral administration of a calcium salt (e.g., IV calcium gluconate), would be expected to restore physiologic amounts of ionized calcium and relieve signs and symptoms of hypocalcemia.100, 101, 125
Bone is the major site of action of etidronate disodium. The drug's principal pharmacologic action is reduction of normal and abnormal bone resorption. Since bone formation is coupled to resorption, bone formation and therefore bone turnover are reduced.
The principal mechanism of action of etidronate disodium in the treatment of hypercalcemia associated with malignant neoplasms is the reduction of abnormal bone resorption.100, 101, 102, 105, 110, 112 The drug does not exhibit direct antineoplastic activity.103, 104 The mechanism of action of etidronate disodium in the treatment of Paget disease of bone and in the prevention of heterotopic ossification is not known. Chemical and in vitro studies show that the drug adsorbs to hydroxyapatite crystals, thereby inhibiting their growth and dissolution; theoretically, it is this action that slows excessive remodeling of pagetic bone and prevents or slows the formation of heterotopic bone during the active stage. In addition, the drug markedly decreases the number of osteoclasts and may have a direct effect on bone cells. The exact mechanism(s) of the antiresorptive action of etidronate disodium has not been clearly determined, but it may involve the drug's effects on hydroxyapatite crystals and/or bone resorbing cells. In patients with Paget disease, etidronate disodium reduces the rate of bone turnover. Decreased rate of bone resorption is characterized by a reduction in elevated urinary hydroxyproline excretion, and reduction in new bone formation is characterized by decreased serum alkaline phosphatase concentrations. Decreased bone turnover also reduces the uptake of radionuclide imaging agents at sites of pagetic involvement. Etidronate disodium reduces the vascularity of pagetic bone, the skin temperature over superficially located pagetic lesions, and the elevated cardiac output that may occur in Paget disease of bone.
In patients receiving oral etidronate disodium at a dosage of 10 or 20 mg/kg daily, mineralization of new osteoid is inhibited, principally in pagetic lesions and to a lesser extent in normal bone; mineralization of ectopic bone matrix also may be delayed. Mineralization returns to normal after discontinuing the drug. Except in a few unusual cases or when etidronate disodium is administered continuously for a prolonged period, the delay in mineralization is not of clinical consequence.101 With oral dosages of 5 mg/kg daily, abnormal accumulation of unmineralized osteoid does not occur.
Studies in animals using murine tumors indicate that, with some types of tumors, etidronate disodium can inhibit bone metastasis following intra-aortic inoculation of tumor cells and inhibit invasion of bone adjacent to tumors.104 The relevance of these findings to humans remains to be established, and further studies are needed.104
Etidronate disodium can increase serum phosphate concentration, apparently as a result of increased renal tubular reabsorption of phosphate. The drug does not interfere with the effects of parathyroid hormone at the renal tubule. Hyperphosphatemia has occurred less frequently following IV use of etidronate disodium (an IV preparation is no longer commercially available in the US) for the treatment of malignancy-associated hypercalcemia than following oral use of the drug for other conditions.100, 101
Etidronate disodium does not substantially affect serum calcium or parathyroid hormone concentrations when used orally for the treatment of Paget disease of bone or for the prevention and treatment of heterotopic ossification. Following IV administration, the drug does not appear to alter renal tubular reabsorption of calcium and does not affect hypercalcemia in patients with hyperparathyroidism in which increased renal tubular reabsorption may be a factor in the hypercalcemia.100 Following IV administration of etidronate disodium in patients with malignancy-associated hypercalcemia, the parathyroid hormone response appears to be variable, but suppressed serum concentrations of the hormone generally return to the normal range as the serum calcium concentration decreases.105
Studies in animals indicate that etidronate disodium does not exhibit immunosuppressive activity.104
Approximately 3% of an oral dose of etidronate is absorbed.125 Oral absorption of etidronate disodium is variable and appears to be dose dependent. The presence of food in the GI tract decreases the extent of absorption of the drug. Following oral administration of etidronate disodium on an empty stomach, approximately 1-1.5% of a 5-mg/kg dose, 2.5% of a 10-mg/kg dose, and 6-10% of a 20-mg/kg dose was absorbed.
Following oral administration, etidronate disodium is rapidly cleared from the blood; about 50% of the amount absorbed is distributed almost exclusively into bone. There is almost no detectable uptake of the drug in soft tissue.101 Preclinical studies indicate that etidronate disodium does not cross the blood-brain barrier.125 It is not known whether etidronate disodium is distributed into milk.
A plasma elimination half-life of 1-6 hours for etidronate has been reported in healthy individuals.125 In animals, clearance of the drug from bone has been estimated to be up to 165 days.125
Etidronate disodium is not metabolized, and approximately half of an absorbed oral dose101 is excreted unchanged in urine within 24 hours.125 Unabsorbed orally administered drug is excreted in feces. Nonrenal clearance is believed to result from uptake of the drug by bone; subsequently, the drug is eliminated slowly via bone turnover.100, 101, 106
Etidronate disodium is a synthetic bisphosphonate (also referred to as diphosphonate) analog of pyrophosphate, a naturally occurring inhibitor of bone metabolism. Unlike pyrophosphate but like alendronate and pamidronate, etidronate disodium is resistant to enzymatic hydrolysis.
Etidronate disodium occurs as a white powder and is freely soluble in water and insoluble in alcohol.
Etidronate disodium tablets should be stored in tight containers at a temperature less than 40°C.125
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 200 mg* | Etidronate Disodium Tablets | |
400 mg* | Etidronate Disodium Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
100. MGI Pharma. Didronel® I.V. Infusion (etidronate disodium) prescribing information. Minnetonka, MN; 1998 Jan.
101. Norwich Eaton Pharmaceuticals, Inc. Didronel® I.V. Infusion (etidronate disodium) background data for review by pharmacy and therapeutic committees. Publication No. 2326-70. Norwich, NY; 1987 Apr.
102. Kanis JA, Urwin GH, Gray RES et al. Effects of intravenous etidronate disodium on skeletal and calcium metabolism. Am J Med . 1987; 82(Suppl 2A):55-70. [PubMed 3103437]
103. Guaitani A, Polentarutti N, Filippeschi S et al. Effects of disodium etidronate in murine tumor models. Eur J Cancer Clin Oncol . 1984; 20:685-93. [PubMed 6428894]
104. Garattini S, Guaitani A, Mantovani A. Effect of etidronate disodium on the interactions between malignancy and bone. Am J Med . 1987; 82(Suppl 2A):29-33. [PubMed 3103435]
105. Jacobs TP, Gordon AC, Silverberg SJ et al. Neoplastic hypercalcemia: physiologic response to intravenous etidronate disodium. Am J Med . 1987; 82(Suppl 2A):42-50. [PubMed 3030098]
106. Powell JH, DeMark BR. Clinical pharmacokinetics of diphosphonates. In: Garattini S, ed. Bone resorption, metastasis, and diphosphonates. New York: Raven Press; 1985:41-9.
107. Altman RD. Long-term follow-up of therapy with intermittent etidronate disodium in Paget's disease of bone. Am J Med . 1985; 79:583-90. [PubMed 3933343]
108. Perry HM III, Droke DM, Avioli LV. Alternate calcitonin and etidronate disodium therapy for Paget's bone disease. Arch Intern Med . 1984; 144:929-33. [PubMed 6424594]
109. Charhon S, Chapuy MC, Valentin-Opran A et al. Intravenous etidronate for spinal cord dysfunction due to Paget's disease. Lancet . 1982; 1:391-2. [PubMed 6120363]
110. Meunier PJ, Chapuy MC, Delmas P et al. Intravenous disodium etidronate therapy in Paget's disease of bone and hypercalcemia of malignancy: effects on biochemical parameters and bone histomorphometry. Am J Med . 1987; 82(Suppl 2A):71-8. [PubMed 3103438]
111. Ryzen E, Martodam RR, Troxell M et al. Intravenous etidronate in the management of malignant hypercalcemia. Arch Intern Med . 1985; 145:449-52. [PubMed 3919667]
112. Hasling C, Charles P, Mosekilde L. Etidronate disodium for treating hypercalcaemia of malignancy: a double blind, placebo-controlled study. Eur J Clin Invest . 1986; 16:433-7. [PubMed 3100312]
113. Zweig JI, Shafer N. Treatment of hypercalcemia with etidronate disodium. JAMA . 1980; 244:437-8. [PubMed 6771418]
114. Mundy GR, Wilkinson R, Heath DA. Comparative study of available medical therapy for hypercalcemia of malignancy. Am J Med . 1983; 74:421-32. [PubMed 6219578]
115. Ringenberg QS, Ritch PS. Efficacy of oral administration of etidronate disodium in maintaining normal serum calcium levels in previously hypercalcemic cancer patients. Clin Ther . 1987; 9:318-25. [PubMed 3111705]
116. Schiller JH, Rasmussen P, Benson AB III et al. Maintenance etidronate in the prevention of malignancy-associated hypercalcemia. Arch Intern Med . 1987; 147:963-6. [PubMed 3107487]
117. Hagg E, Eklund M, Torring O. Disodium etidronate in hypercalcaemia due to immobilization. BMJ . 1984; 288:607-8. [PubMed 6421398][PubMedCentral]
118. Merli GJ, McElwain GE, Adler AG et al. Immobilization hypercalcemia in acute spinal cord injury treated with etidronate. Arch Intern Med . 1984; 144:1286-8. [PubMed 6428341]
119. Meythaler JM, Korkor AB, Nanda T et al. Immobilization hypercalcemia associated with Landry-Guillain-Barré syndrome: successful therapy with combined calcitonin and etidronate. Arch Intern Med . 1986; 146:1567-71. [PubMed 3089187]
120. Anon. Medical management of primary hyperparathyroidism. Lancet . 1984; 2:727-8. [PubMed 6148476]
121. Licata AA, O'Hanlon E. Treatment of hyperparathyroidism with etidronate disodium. JAMA . 1983; 249:2063-4. [PubMed 6403720]
122. Scher HI, Yagoda A. Bone metastases: pathogenesis, treatment, and rationale for use of resorption inhibitors. Am J Med . 1987; 82(Suppl 2A):6-28. [PubMed 3548343]
123. Bounameux HM, Schifferli J, Montani JP et al. Renal failure associated with intravenous diphosphonates. Lancet . 1983; 1:471. [PubMed 6131186]
124. Boyce BF, Fogelman I, Ralston S et al. Focal osteomalacia due to low-dose diphosphonate therapy in Paget's disease. Lancet . 1984; 1:821-4. [PubMed 6143140]
125. Procter & Gamble Pharmaceuticals. Didronel® (etidronate disodium) tablets prescribing information. Cincinnati, OH; 2009 Dec.
126. Francis MD, Slough CL. Acute intravenous infusion of disodium dihydrogen (1-hydroxyethylidene)diphosphonate: mechanism of toxicity. J Pharm Sci . 1984; 73:1097-1100. [PubMed 6436463]
127. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.
128. Procter & Gamble Pharmaceuticals. Actonel® (risedronate sodium) tablets prescribing information. Cincinnati, OH; 2008 Apr.
129. Miller PD, Brown JP, Siris ES et al. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget’s disease of bone. Am J Med . 1999; 106:513-20. [PubMed 10335722]
130. Plotkin LI, Weinstein RS, Parfitt AM et al. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest . 1999; 104:1363-74. [PubMed 10562298][PubMedCentral]
131. Adachi JD, Bensen WG, Brown J et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med . 1997; 337:382-7. [PubMed 9241127]
132. Roux C, Oriente P, Laan R et al. Randomized trial of the effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. J Clin Endocrinol Metab . 1998; 83:1128-33. [PubMed 9543129]
133. Adachi JD, Saag KG, Delmas PD et al. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum . 2001; 44:202-11. [PubMed 11212161]
134. Reid DM, Hughes RA, Laan RF et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. J Bone Miner Res . 2000; 15:1006-20. [PubMed 10841169]
135. Diamond T, McGuigan L, Barbagallo S et al. Cyclical etidronate plus ergocalciferol prevents glucocorticoid-induced bone loss in postmenopausal women. Am J Med . 1995; 98:459-63. [PubMed 7733124]
136. Cohen S, Levy RM, Keller M et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum . 1999; 42:2309-18. [PubMed 10555025]
137. Wallach S, Cohen S, Reid DM et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int . 2000; 67:277-85. [PubMed 11000340]
140. Sambrook PN. Corticosteroid osteoporosis: practical implications of recent trials. J Bone Miner Res . 2000; 15:1645-9. [PubMed 10976984]
141. Jenkins EA, Walker-Bone KE, Wood A et al. The prevention of corticosteroid-induced bone loss with intermittent cyclical etidronate. Scand J Rheumatol . 1999; 28:152-6. [PubMed 10380836]
142. Hanley DA, Ioannidis G, Adachi JD. Etridronate therapy in the treatment and prevention of osteoporosis. J Clin Densitom . 2000; 3:79-95. [PubMed 10745305]
143. Sebaldt RJ, Ioannidis G, Adachi JD et al. 36 month intermittent cyclical etidronate treatment in patients with established corticosteroid induced osteoporosis. J Rheumatol . 1999; 26:1545-9. [PubMed 10405943]
144. Cortet B, Hachulla E, Barton I et al. Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid-induced bone loss in patients with inflammatory rheumatic diseases. A randomized study. Rev Rhum Engl Ed . 1999; 66:214-9. [PubMed 10339777]
145. Pitt P, Li F, Todd P et al. A double blind placebo controlled study to determine the effects of intermittent cyclical etidronate on bone mineral density in patients on long-term oral corticosteroid treatment. Thorax . 1998; 53:351-6. [PubMed 9708225][PubMedCentral]
146. Struys A, Snelder AA, Mulder H. Cyclical etidronate reverses bone loss of the spine and proximal femur in patients with established corticosteroid-induced osteoporosis. Am J Med . 1995; 99:235-42. [PubMed 7653482]
147. Ruggiero SL, Mehrotra B, Rosenberg TJ et al. Osteonecrosis of the jaw associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg . 2004; 62:527-34. [PubMed 15122554]
148. Novartis. Zometa® (zoledronic acid) injection prescribing information. East Hanover, NJ; 2008 Mar.
149. Hohneker JA. Dear doctor letter regarding osteonecrosis of the jaw in patients with cancer receiving bisphophonates. East Hanover, NJ: Novartis; 2004 September 24.
150. Ruggiero SL, Mehrotra B. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med . 2004; 351:191.
151. Bone HG, Santora AC. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med . 2004; 351:191-2.
152. Food and Drug Administration. Center for Drug Evaluation and Research. Dugs@FDA: didronel. From FDA website. Accessed 2005 Jan 4. [Web]
153. Center for Drug Evaluation and Research, Food and Drug Administration. FDA Alert: Information for healthcare professionals on bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa). 2008 Jan 7. From FDA website. Accessed 2008 Oct 28. [Web]
154. Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med . 2005; 165:346-7. [PubMed 15710802]
155. Center for Drug Evaluation and Research, Food and Drug Administration. Update of safety review follow-up to the October 1, 2007 early communication about the ongoing safety review of bisphosphonates. Bisphosphonates: alendronate (Fosamax, Fosamax plus D) etidronate (Didronel), ibandronate (Boniva), Pamidronate (Aredia), risedronate (Actonel, Actonel w/calcium), tiludronate (Skelid), and zoledronic acid (Reclast, Zometa). 2008 Nov 12. From FDA website. Accessed 2008 Nov 21. [Web]
156. Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med . 2009; 360:89-90. Letter. [PubMed 19118315]
157. Food and Drug Administration. FDA Drug Safety Communication: Safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. Silver Spring, MD; 2010 Oct 13. From FDA web site. Accessed 2010 Nov 4. [Web]
158. Shane E, Burr D, Ebeling PR et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res . 2010; 25:2267-94. [PubMed 20842676]
159. Food and Drug Administration. FDA News Release: Possible increased risk of thigh bone fracture with bisphosphonates. Silver Spring, MD; 2010 Oct 13. From FDA website. Accessed 2010 Nov 4. [Web]
160. Food and Drug Administration. FDA drug safety communication: Ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer. Rockville, MD; 2011 July 21. Available from FDA website. Accessed 2011 Sept 12. [Web]
161. Green J, Czanner G, Reeves G et al. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ . 2010; 341:c4444. [PubMed 20813820][PubMedCentral]
162. Cardwell CR, Abnet CC, Cantwell MM et al. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA . 2010; 304:657-63. [PubMed 20699457][PubMedCentral]
163. Abrahamsen B, Eiken P, Eastell R. More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med . 2009; 360:1789; author reply 1791-2.
164. Abrahamsen B, et al. The risk of oesophageal and cancer incidence and mortality in alendronate users: a national cohort study. Presented at the 3rd Joint Meeting of the European Calcified Tissue Society and the International Bone and Mineral Society. Athens, Greece: May 10, 2011. Abstract No. 0C29.
165. Solomon DH, Patrick A, Brookhart MA. More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med . 2009; 360:1789-90; author reply 1791-2. [PubMed 19391255]
166. Grossman JM, Gordon R, Ranganath VK et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) . 2010; 62:1515-26. [PubMed 20662044]
167. Kanis JA, Oden A, Johansson H et al. FRAX and its applications to clinical practice. Bone . 2009; 44:734-43. [PubMed 19195497]
173. Kasting GB, Francis MD. Retention of etidronate in human, dog, and rat. J Bone Miner Res . 1992; 7:513-22. [PubMed 1615760]
622. Buckley L, Guyatt G, Fink HA et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol . 2017; 69:1521-1537. [PubMed 28585373]