|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
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
(ris ED roe nate)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Actonel®: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM241447.pdf
Atelvia™: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM241450.pdf
REMS Components
Medication Guide
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Actonel®: Treatment of Paget's disease of the bone; treatment and prevention of glucocorticoid-induced osteoporosis; treatment and prevention of osteoporosis in postmenopausal women; treatment of osteoporosis in men
Atelvia™: Treatment of osteoporosis in postmenopausal women
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic and nonteratogenic embryo/fetal effects have been reported in animal studies. There are no adequate and well-controlled studies in pregnant women. 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/not recommended
Breast-Feeding Considerations
The manufacturer recommends discontinuing nursing or discontinuing risedronate.
Contraindications
Hypersensitivity to risedronate, bisphosphonates, or any component of the formulation; hypocalcemia; inability to stand or sit upright for at least 30 minutes; abnormalities of the esophagus which delay esophageal emptying, such as stricture or achalasia
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: 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.
• Gastrointestinal mucosa irritation: May cause irritation to upper gastrointestinal mucosa. Dysphagia, esophagitis, esophageal or gastric 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 if new or worsening symptoms occur.
• 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:
• Glucocorticoid-induced osteoporosis: Evaluate sex steroid hormonal status prior to treatment initiation; consider appropriate hormone replacement if necessary.
• Hypocalcemia: Before initiation of therapy hypocalcemia must be corrected; ensure adequate calcium and vitamin D intake, especially for patients with Paget's disease in whom the pretreatment rate of bone turnover may be greatly elevated.
• Renal impairment: Use with caution in patients with renal impairment (not recommended in patients with a Clcr <30 mL/minute).
Special populations:
• Pediatrics: Not approved for use in pediatric patients with osteogenesis imperfecta due to lack of efficacy in reducing the risk of fracture.
Adverse Reactions
Frequency may vary with product, dose, and indication.
>10%:
Cardiovascular: Hypertension (11%)
Central nervous system: Headache (3% to 18%)
Dermatologic: Rash (8% to 12%)
Endocrine & metabolic: Serum PTH levels increased (transient; <30%)
Gastrointestinal: Diarrhea (5% to 20%), nausea (4% to 13%), constipation (3% to 13%), abdominal pain (2% to 12%), dyspepsia (4% to 11%)
Genitourinary: Urinary tract infection (11%)
Neuromuscular & skeletal: Arthralgia (7% to 33%), back pain (6% to 28%)
Miscellaneous: Infection (≤31%)
1% to 10%:
Cardiovascular: Peripheral edema (8%), chest pain (5% to 7%), arrhythmia (2%)
Central nervous system: Depression (7%), dizziness (3% to 7%)
Endocrine & metabolic: Hypocalcemia (≤5%), hypophosphatemia (<3%)
Gastrointestinal: Vomiting (2% to 5%), gastritis (3%), duodenitis (≤1%), glossitis (≤1%)
Genitourinary: Prostatic hyperplasia (5%; benign), nephrolithiasis (3%)
Neuromuscular & skeletal: Joint disorder (7%), myalgia (2% to 7%), neck pain (5%), muscle spasm (1% to 2%)
Ocular: Cataract (7%)
Respiratory: Bronchitis (3% to 10%), pharyngitis (6%), rhinitis (6%), dyspnea (4%)
Miscellaneous: Flu-like syndrome (10%), acute phase reaction (≤8%; includes fever, influenza-like illness)
<1%, postmarketing, and/or case reports: Allergic reaction, angioedema, arthritis, bullous skin reaction, cough, diaphyseal femur fracture, dysphagia, esophageal cancer, esophageal ulcer, esophagitis, gastric ulcer, hypersensitivity reaction, iritis, joint pain, liver function test abnormality, musculoskeletal pain (rarely severe or incapacitating), osteonecrosis (primarily of the jaw), sinusitis, subtrochanteric femur fracture, uveitis
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
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).
Food: Food reduces absorption (similar to other bisphosphonates); mean oral bioavailability is decreased when given with food.
Storage
Store at room temperature of 20°C to 25°C (68°F to 77°F).
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
Onset of action: May require weeks
Absorption: Rapid
Distribution: Vd: 13.8 L/kg
Protein binding: ~24%
Metabolism: None
Bioavailability: Poor, ~0.54% to 0.75%
Half-life elimination: Initial: 1.5 hours; Terminal: 480-561 hours
Time to peak, serum: 1-3 hours
Excretion: Urine (up to 85%); feces (as unabsorbed drug)
Dosage
Oral: Adults: Note: Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.
Immediate release tablet:
Paget's disease of bone: 30 mg once daily for 2 months
Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than one course of retreatment.
Osteoporosis (postmenopausal) prevention and treatment: 5 mg once daily or 35 mg once weekly or 150 mg once a month
Osteoporosis (male) treatment: 35 mg once weekly
Osteoporosis (glucocorticoid-induced) prevention and treatment: 5 mg once daily
Delayed release tablet: Osteoporosis (postmenopausal) treatment: 35 mg once weekly
Dosage adjustment in renal impairment:
Clcr ≥30 mL/minute: No adjustment required
Clcr <30 mL/minute: Not recommended for use
Dosage adjustment in hepatic impairment: No studies performed in hepatic impairment; no dosage adjustment necessary due to lack of hepatic metabolism
Administration: Oral
Note: Avoid administration of oral calcium supplements, antacids, magnesium supplements/laxatives, and iron preparations within 30 minutes of risedronate administration.
Immediate release tablet: Risedronate immediate release tablets must be taken on an empty stomach with a full glass (6-8 oz) of plain water (not mineral water) at least 30 minutes before any food, drink, or other medications orally to avoid interference with absorption. Patient must remain sitting upright or standing for at least 30 minutes after taking (to reduce esophageal irritation). Tablet should be swallowed whole; do not crush or chew.
Delayed release tablet: Risedronate delayed release tablets must be taken with at least 4 oz of plain water (not mineral water) immediately after breakfast. Patient must remain sitting upright or standing for at least 30 minutes after taking (to reduce esophageal irritation). Tablet should be swallowed whole; do not cut, split, crush, or chew.
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 thereafter (6-12 months post-baseline if combined glucocorticoid and risedronate treatment, then every 2 years thereafter); annual measurements of height and weight, assessment of chronic back pain; serum calcium and 25(OH)D; consider measuring biochemical markers of bone turnover
Paget's disease: Alkaline phosphatase; pain; serum calcium and 25(OH)D
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. Take immediate release tablet with at least 6 oz of plain water (not mineral water) ≥30 minutes before the first food or drink of the day other than water. Take delayed release tablet with at least 4 ounces of plain water immediately after breakfast.
Patient Education
Stay in upright sitting or standing position for 30 minutes following administration to reduce potential for esophageal irritation. Take immediate release tablets with a full glass (6-8 oz) of water on an empty stomach at least 30 minutes before eating or taking anything else. Take delayed release tablets with at least 4 ounces of water immediately after breakfast. Do not cut, crush, or chew tablets. Certain dental procedures should be avoided if possible while you are taking this medication. You may experience temporary nausea or vomiting, diarrhea, or bone pain. Report persistent muscle or bone pain; leg cramps; muscle twitching; unusual fever; seizures; difficulty breathing; rash; bloody stool; or pain in mouth, jaws, or teeth.
Geriatric Considerations
No dosage adjustment required if Clcr ≥30 mL/minute. Since elderly often receive diuretics, evaluate electrolyte status periodically due to the drug class (bisphosphonates). Ensure that immobilized patients remain sitting upright for at least 30 minutes after swallowing tablet. 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 cause depression, insomnia, anxiety, and dizziness
Mental Health: Effects on Psychiatric Treatment
Nausea and diarrhea are common; concomitant use with SSRIs, lithium, valproic acid, or carbamazepine may produce additive effects
Nursing: Physical Assessment/Monitoring
Assess history for any previous adverse response to bisphosphonates 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.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral, as sodium:
Actonel®: 5 mg, 30 mg, 35 mg, 150 mg
Tablet, delayed release, oral, as sodium:
Atelvia™: 35 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Actonel)
5 mg (30): $131.77
30 mg (10): $273.99
35 mg (4): $126.47
150 mg (1): $132.99
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.
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
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.
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
Content last modified May 2011
| 
