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Special Alerts
Bisphosphonates for Osteoporosis: Risk of Atypical Fracture
October 2010
The U.S. Food and Drug Administration (FDA) has reviewed all available data concerning the association between the use of bisphosphonates for osteoporosis (ie, alendronate, ibandronate, risedronate, zoledronic acid) and the risk of atypical fractures of the thigh (subtrochanteric and diaphyseal femur fractures). Subtrochanteric femur fractures occur in the bone just below the hip joint; diaphyseal femur fractures occur in the long part of the thigh bone. These fractures are very uncommon, occurring as <1% of all femur fractures. It is unclear if bisphosphonates are the cause, but these unusual fractures have been predominantly reported in patients taking bisphosphonates. In some cases, patients may experience dull, aching thigh pain prior to the fracture occurring. In Canada, an ongoing review is being conducted by Health Canada to similarly evaluate this safety information.
Patients are encouraged to consult their healthcare providers for new hip or thigh pain. The FDA and Health Canada are recommending that patients continue these medications unless their healthcare providers discontinue the treatment. Healthcare providers should evaluate patients with new complaints of thigh or groin pain, and discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture. Reports of these adverse events should be made in the U.S. to the FDA, and in Canada, to Health Canada's Vigilance Program.
Based on their safety review, the FDA will require a medication guide to be given to patients when they pick up their bisphosphonate prescription. The FDA is continuing its evaluation of data concerning the safety and efficacy of long-term use (longer than 3-5 years) of bisphosphonates used for osteoporosis. Manufacturers are updating product labeling to reflect the risk of atypical fractures.
Further information may be found at:
US: http://www.fda.gov/Drugs/DrugSafety/ucm229009.htm
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2010/2010_175-eng.php
Pronunciation
(a LEN droe nate)
Generic Available (U.S.)
Yes: Tablet
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM241519.pdf, must be dispensed with this medication.
REMS Components
Medication Guide
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment and prevention of osteoporosis in postmenopausal females; treatment of osteoporosis in males; Paget's disease of the bone in patients who are symptomatic, at risk for future complications, or with alkaline phosphatase ≥2 times the upper limit of normal; treatment of glucocorticoid-induced osteoporosis in males and females with low bone mineral density who are receiving a daily dosage ≥7.5 mg of prednisone (or equivalent)
Pregnancy Risk Factor
C
Pregnancy Considerations
Safety and efficacy have not been established in pregnant women. Animal studies have shown delays in delivery and fetal/neonatal death (secondary to hypocalcemia). Bisphosphonates are incorporated into the bone matrix and gradually released over time. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy. Based on limited case reports with pamidronate, serum calcium levels in the newborn may be altered if administered during pregnancy.
Lactation
Excretion in breast milk unknown/use caution
Contraindications
Hypersensitivity to alendronate, other bisphosphonates, or any component of the formulation; hypocalcemia; abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia; inability to stand or sit upright for at least 30 minutes; oral solution should not be used in patients at risk of aspiration
Warnings/Precautions
Concerns related to adverse effects:
• Bone fractures: Atypical femur fractures have been reported in patients receiving bisphosphonates for treatment/prevention of osteoporosis. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). Some patients experience prodromal pain weeks or months before the fracture occurs. It is unclear if bisphosphonate therapy is the cause for these fractures, although the majority have been reported in patients taking bisphosphonates. Patients receiving long-term (>3-5 years) therapy may be at an increased risk. Discontinue bisphosphonate therapy in patients who develop a femoral shaft fracture.
• Bone/joint/muscle pain: 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.
• Gastrointestinal mucosa irritation: May cause irritation to upper gastrointestinal 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.
• Hypocalcemia: Hypocalcemia has been reported with the use of bisphosphonates. Prior to therapy initiation, hypocalcemia must be corrected; ensure adequate calcium and vitamin D intake.
• Osteonecrosis of the jaw (ONJ): ONJ has been reported in patients receiving bisphosphonates. Risk factors include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery); a diagnosis of cancer, with concomitant chemotherapy or corticosteroids; poor oral hygiene, ill-fitting dentures; and comorbid disorders (anemia, coagulopathy, infection, pre-existing dental disease). Most reported cases occurred after I.V. bisphosphonate therapy; however, cases have been reported following oral therapy. A dental exam and preventative dentistry should be performed prior to placing patients with risk factors on chronic bisphosphonate therapy. The manufacturer's labeling states that discontinuing bisphosphonates in patients requiring invasive dental procedures may reduce the risk of ONJ. However, other experts suggest that there is no evidence that discontinuing therapy reduces the risk of developing ONJ (Assael, 2009). The benefit/risk must be assessed by the treating physician and/or dentist/surgeon prior to any invasive dental procedure. Patients developing ONJ while on bisphosphonates should receive care by an oral surgeon.
Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment (not recommended for use in patients with Clcr <35 mL/minute).
Adverse Reactions
Note: Incidence of adverse effects (mostly GI) increases significantly in patients treated for Paget's disease at 40 mg/day.
>10%: Endocrine & metabolic: Hypocalcemia (transient, mild, 18%); hypophosphatemia (transient, mild, 10%)
1% to 10%:
Central nervous system: Headache (up to 3%)
Gastrointestinal: Abdominal pain (1% to 7%), acid reflux (1% to 4%), dyspepsia (1% to 4%), nausea (1% to 4%), flatulence (up to 4%), diarrhea (1% to 3%), gastroesophageal reflux disease (1% to 3%), constipation (up to 3%), esophageal ulcer (up to 2%), abdominal distension (up to 1%), gastritis (up to 1%), vomiting (up to 1%), dysphagia (up to 1%), gastric ulcer (1%), melena (1%)
Neuromuscular & skeletal: Musculoskeletal pain (up to 6%), muscle cramps (up to 1%)
<1%, postmarketing, and/or case reports: Alopecia, anastomotic ulcer, angioedema, atrial fibrillation; bone, muscle, or joint pain (occasionally severe, considered incapacitating in rare cases); diaphyseal femur fracture, dizziness, duodenal ulcer, episcleritis, erythema, esophageal cancer, esophageal erosions, esophageal perforation, esophageal stricture, esophageal ulcers, esophagitis, fever, flu-like syndrome, hypersensitivity reactions, hypocalcemia (symptomatic), joint swelling, low-energy femoral shaft and subtrochanteric fractures, lymphocytopenia, malaise, myalgia, oropharyngeal ulceration, osteonecrosis (jaw), peripheral edema, photosensitivity (rare), pruritus, rash, scleritis (rare), Stevens-Johnson syndrome, taste perversion, toxic epidermal necrolysis, urticaria, uveitis (rare), vertigo, weakness
Drug Interactions
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Antacids: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of antacids containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Magaldrate; Sodium Bicarbonate. Risk D: Consider therapy modification
Aspirin: May enhance the adverse/toxic effect of Alendronate. Specifically gastrointestinal adverse events. Risk C: Monitor therapy
Calcium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral calcium supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after ibandronate; or 30 minutes after alendronate/risedronate. Risk D: Consider therapy modification
Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Iron Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral iron supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk D: Consider therapy modification
Magnesium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral magnesium salts within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after ibandronate; or 30 minutes after alendronate/risedronate. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy
Phosphate Supplements: Bisphosphonate Derivatives may enhance the hypocalcemic effect of Phosphate Supplements. Risk C: Monitor therapy
Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase risk of osteoporosis and gastric irritation).
Food: All food and beverages interfere with absorption. Coadministration with caffeine may reduce alendronate efficacy. Coadministration with dairy products may decrease alendronate absorption. Beverages (especially orange juice and coffee) and food may reduce the absorption of alendronate as much as 60%.
Storage
Store tablets and oral solution at room temperature of 15°C to 30°C (59°F to 86°F). Keep in well-closed container.
Mechanism of Action
A bisphosphonate which inhibits bone resorption via actions on osteoclasts or on osteoclast precursors; decreases the rate of bone resorption, leading to an indirect increase in bone mineral density. In Paget's disease, characterized by disordered resorption and formation of bone, inhibition of resorption leads to an indirect decrease in bone formation; but the newly-formed bone has a more normal architecture.
Pharmacodynamics/Kinetics
Distribution: 28 L (exclusive of bone)
Protein binding: ~78%
Metabolism: None
Bioavailability: Fasting: 0.6%; reduced up to 60% with food or drink
Half-life elimination: Exceeds 10 years
Excretion: Urine; feces (as unabsorbed drug)
Dosage
Oral: Adults: Note: Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.
Osteoporosis in postmenopausal females:
Prophylaxis: 5 mg once daily or 35 mg once weekly
Treatment: 10 mg once daily or 70 mg once weekly
Osteoporosis in males: 10 mg once daily or 70 mg once weekly
Osteoporosis secondary to glucocorticoids in males and females: Treatment: 5 mg once daily; a dose of 10 mg once daily should be used in postmenopausal females who are not receiving estrogen.
Paget's disease of bone in males and females: 40 mg once daily for 6 months
Retreatment: Relapses during the 12 months following therapy occurred in 9% of patients who responded to treatment. Specific retreatment data are not available. Following a 6-month post-treatment evaluation period, retreatment with alendronate may be considered in patients who have relapsed based on increases in serum alkaline phosphatase, which should be measured periodically. Retreatment may also be considered in those who failed to normalize their serum alkaline phosphatase.
Elderly: No dosage adjustment is necessary
Dosage adjustment in renal impairment:
Clcr 35-60 mL/minute: None necessary
Clcr <35 mL/minute: Alendronate is not recommended due to lack of experience
Dosage adjustment in hepatic impairment: None necessary
Administration: Oral
Alendronate must be taken with plain water (tablets 6-8 oz; oral solution follow with 2 oz) first thing in the morning and ≥30 minutes before the first food, beverage, or other medication of the day. Do not take with mineral water or with other beverages. Patients should be instructed to stay upright (not to lie down) for at least 30 minutes and until after first food of the day (to reduce esophageal irritation).
Monitoring Parameters
Osteoporosis: Bone mineral density as measured by central dual-energy x-ray absorptiometry (DXA) of the hip or spine (prior to initiation of therapy and at least every 2 years; after 6-12 months of combined glucocorticoid and alendronate treatment); annual measurements of height and weight, assessment of chronic back pain; serum calcium and 25(OH)D; may consider monitoring biochemical markers of bone turnover
Paget's disease: Alkaline phosphatase; pain; serum calcium and 25(OH)D
Reference Range
Calcium (total): Adults: 9.0-11.0 mg/dL (2.05-2.54 mmol/L), may slightly decrease with aging; phosphorus: 2.5-4.5 mg/dL (0.81-1.45 mmol/L)
Test Interactions
Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.
Dietary Considerations
Ensure adequate calcium and vitamin D intake; women and men >50 years of age should consume 1200-1500 mg/day of elemental calcium and 800-1000 int. units/day of vitamin D. Wait at least 30 minutes after taking alendronate before taking any supplement. Alendronate must be taken with plain water first thing in the morning and at least 30 minutes before the first food or beverage of the day. Do not take with mineral water or with other beverages.
Patient Education
Take first thing in the morning, at least 30 minutes before the first food or beverage of the day. Take tablets with a full 6- to 8-ounce glass of water; follow solution with 2 ounces of water. Wait at least 30 minutes after taking alendronate before eating or drinking anything else. Stay in sitting or standing position for 30 minutes following administration and until after the first food of the day to reduce potential for esophageal irritation. Consult prescriber to determine necessity of lifestyle changes (eg, decreased smoking, decreased alcohol intake). Consult prescriber before having any dental procedures; inform dentist that you are taking this medication. You may experience flatulence, bloating, nausea, acid regurgitation, temporary bone pain, or muscle cramps. Report persistent muscle or bone pain or leg cramps; persistent unresolved GI pain or upset; unusual fever or chills; or pain in mouth, jaws, or teeth.
Geriatric Considerations
Since many elderly patients receive diuretics, evaluation of electrolyte status (calcium, phosphate, magnesium, potassium) may need to be done periodically due to the drug class (bisphosphonate). The elderly are frequently treated long-term for osteoporosis and patients should be advised to report any lower extremity pain that cannot be explained or lasts for more than a week.
Dental Health: Effects on Dental Treatment
Osteonecrosis of the jaw (ONJ), generally associated with local infection and/or tooth extraction and often with delayed healing, has been reported in patients taking bisphosphonates. Symptoms included nonhealing extraction socket or an exposed jawbone. Most reported cases of bisphosphonate-associated osteonecrosis have been in cancer patients treated with intravenous bisphosphonates. However, some have occurred in patients with postmenopausal osteoporosis taking oral bisphosphonates. Dental surgery, particularly tooth extraction, may increase the risk for ONJ. Patients who develop ONJ while on bisphosphonate therapy should receive care by an oral surgeon. See Dental Health Professional Considerations.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
According to the 2008 report by the American Dental Association (ADA), the incidence of osteonecrosis of the jawbone associated with oral bisphosphonate therapy remains low. It was also stated that the benefits of using oral bisphosphonates to prevent osteoporosis significantly outweighs the small risk of developing bisphosphonate-associated osteonecrosis (Edwards, 2008). The full 26 page report can be accessed at http://www.ada.org/sections/professionalResources/pdfs/topics_osteonecrosis_bisphosphonate_report.pdf.
The ADA review stated the incidence of oral bisphosphonate-associated osteonecrosis of the jaw was one case for every 140,000 person-years exposure to oral bisphosphonates (ADA, 2006). This figure was based on information received from Merck & Co citing 170 worldwide cases for alendronate (Fosamax®). In addition, Procter & Gamble Pharmaceuticals has cited 20 cases for risedronate (Actonel®) and Roche Laboratories, Inc has cited one case for ibandronate (Boniva®).
In addition, the ADA 2008 report reiterates that the risk of osteonecrosis of the jawbone with oral bisphosphonates is minute compared to the risks with intravenous bisphosphonates therapy in cancer patients. The ADA cites an ~20% incidence in patients receiving bisphosphonates intravenously for cancer therapy. Fewer than 10% of all cases of bisphosphonate-associated osteonecrosis of the jaw occurs in patients taking the oral drugs.
Information on alendronate (Fosamax®) use in Australia and the incidence of ONJ has been reported (Mavrokokki, 2007). A survey form was sent to all of the Australian members of the Australian and New Zealand Association of Oral and Maxillofacial Surgeons requesting cases that they had identified as ONJ in 2004 and 2005. The definition of ONJ for the survey was an area of exposed bone in the jawbone that failed to heal within 6 weeks in patients taking bisphosphonates for bone disease. The frequency of ONJ in osteoporotic patients, mainly taking weekly oral alendronate, was 1 in 8470 to 1 in 2260 (0.01% to 0.04%) patients. If extractions were carried out, the calculated frequency was 1 in 1130 to 1 in 296 (0.09% to 0.34%) patients. The minimum values in these cases were determined from the survey, whereas, the maximum values were extrapolated from survey data. The median time to onset of ONJ in alendronate patients was 24 months.
A 2010 study reported the prevalence of osteonecrosis of the jaw in patients using alendronate-type drugs was 1 out of 952 patients or ~0.1% (Lo, 2010). The study's protocol involved a survey mailed out to 13,946 members of Kaiser Permanente of Northern California healthcare delivery system; 8572 patients responded to the survey. Investigators identified respondents reporting oral problems and dental symptoms. These respondents were then interviewed by telephone for presence of dental problems including exposed bone, gingival sores, moderate periodontal disease, and persistent symptoms or complications after dental procedures. Those selected were then invited for an examination or to have their dental records reviewed. The diagnosis of ONJ was made according to the 2006 American Association of Oral and Maxillofacial Surgeons criteria which required treatment with a bisphosphonate, exposed bone in the maxillofacial region lasting >8 weeks, and no radiotherapy involving the jaw. Of the 8572 respondents, 9 cases of ONJ were identified; 5 had developed ONJ spontaneously and 4 developed ONJ after tooth extraction. Specific oral bisphosphonates were not identified. When extrapolated to patient-years of bisphosphonate exposure, this prevalence rate of 0.1% equates to a frequency of 28 cases per 100,000 person-years of oral bisphosphonate treatment.
Mental Health: Effects on Mental Status
May rarely cause dizziness, weakness, and malaise
Mental Health: Effects on Psychiatric Treatment
May produce GI side effects; concomitant use with SSRIs, carbamazepine, valproic acid, and lithium may produce additive effects
Nursing: Physical Assessment/Monitoring
Assess history for any previous adverse response to bisphosphonate therapy and ability to comply with administration instructions. Use caution with renal impairment. Correct any hypocalcemia prior to beginning treatment. Patients at risk for osteonecrosis of the jaw (eg, chemotherapy, corticosteroids, poor oral hygiene) should have dental exams; necessary preventive dentistry should be done before beginning bisphosphonate therapy. Monitor for immediate or long-term musculoskeletal pain. Teach patient specific administration directions. Instruct patient in lifestyle and dietary changes that will have a beneficial impact.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, oral:
Fosamax®: 70 mg/75 mL (75 mL [DSC]) [raspberry flavor]
Tablet, oral: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg
Fosamax®: 5 mg [DSC], 10 mg, 35 mg [DSC], 40 mg [DSC], 70 mg
Pricing: U.S. (www.drugstore.com)
Solution (Fosamax)
70 mg/75 mL (75): $34.75
Tablets (Alendronate Sodium)
5 mg (100): $255.98
10 mg (100): $240.00
40 mg (30): $179.99
Tablets (Fosamax)
5 mg (30): $91.92
10 mg (30): $95.12
35 mg (4): $87.66
70 mg (4): $101.99
References
American Dental Association Council on Scientific Affairs, “Dental Management of Patients Receiving Oral Bisphosphonate Therapy: Expert Panel Recommendations,” J Am Dent Assoc, 2006, 137(8):1144-50. Available at http://jada.ada.org/cgi/content/full/137/8/1144
Assael LA, “Oral Bisphosphonates as a Cause of Bisphosphonate-Related Osteonecrosis of the Jaws: Clinical Findings, Assessment of Risks, and Preventive Strategies,” J Oral Maxillofac Surg, 2009, 67(5 Suppl):35-43.
Author Unknown, “Safety Update: Bone-Building Drugs: Risks Explained,” Consum Rep Health, 2006, 18(5):3.
Cartsos VM, Zhu S, and Zavras AI, “Bisphosphonate Use and the Risk of Adverse Jaw Outcomes: A Medical Claims Study of 714,217 People,” J Am Dent Assoc, 2008, 139(1):23-30.
Chesnut CH 3rd, McClung MR, Ensrud KE, et al, “Alendronate Treatment of the Postmenopausal Osteoporatic Woman: Effect of Multiple Dosages on Bone Mass and Bone Remodeling,” Am J Med, 1995, 99(2):144-52.
Edwards BJ, Hellstein JW, Jacobsen PL, et al, “Updated Recommendations for Managing the Care of Patients Receiving Oral Bisphosphonate Therapy: An Advisory Statement From the American Dental Association Council on Scientific Affairs,” J Am Dent Assoc, 2008, 139(12):1674-7.
French AE, Kaplan N, Lishner M, et al, “Taking Bisphosphonates During Pregnancy,” Can Fam Physician, 2003, 49:1281-2.
Lo JC, O'Ryan FS, Gordon NP, et al, “Prevalence of Osteonecrosis of the Jaw in Patients With Oral Bisphosphonate Exposure,” J Oral Maxillofac Surg, 2010, 68(2):243-53.
“Management of Osteoporosis in Postmenopausal Women: 2010 Position Statement of The North American Menopause Society,” Menopause, 2010, 17(1):25-54.
Marx RE, Sawatari Y, Fortin M, et al, “Bisphosphonate-Induced Exposed Bone (Osteonecrosis/Osteopetrosis) of the Jaws: Risk Factors, Recognition, Prevention, and Treatment,” J Oral Maxillofac Surg, 2005, 63(11):1567-75.
Mavrokokki T, Cheng A, Stein B, et al, “Nature and Frequency of Bisphosphonate-Associated Osteonecrosis of the Jaws in Australia,” J Oral Maxillofac Surg, 2007, 65(3):415-23.
National Osteoporosis Foundation, “Clinician's Guide to Prevention and Treatment of Osteoporosis,” Washington, DC, 2010. Available at http://www.nof.org
Orwoll E, Ettinger M, Weiss S, et al, “Alendronate for the Treatment of Osteoporosis in Men,” N Engl J Med, 2000, 343(9):604-10.
Ralston SH, “Pathogenesis of Paget's Disease of Bone,” Bone, 2008, 43(5):819-25.
Sellmeyer DE, “Atypical Fractures as a Potential Complication of Long-term Bisphosphonate Therapy,” JAMA, 2010, 304(13):1480-4.
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(11):2267-94.
Watts NB, “Treatment of Osteoporosis With Bisphosphonates,” Rheum Dis Clin North Am, 1994, 20(3):717-34.
Whyte MP, “Clinical Practice. Paget's Disease of Bone,” N Engl J Med, 2006, 355(6):593-600.
Wysowski DK, “Reports of Esophageal Cancer With Oral Bisphosphonate Use,” N Engl J Med, 2009, 360(1):89-90.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
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