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Risedronate (Monograph)

Brand names: Actonel, Atelvia
Drug class: Bone Resorption Inhibitors
- Bone Resorption Inhibitors
VA class: HS900
Chemical name: [1-hydroxy-2-(3-pyridinyl)ethylidene]bis-phosphonic acid monosodium salt
Molecular formula: C7H10NNaO7P2
CAS number: 115436-72-1

Medically reviewed by Drugs.com on Mar 4, 2024. Written by ASHP.

Introduction

Synthetic bisphosphonate; bone resorption inhibitor.1 2 5 6 8 9 12 13 14

Uses for Risedronate

Osteoporosis

Prevention of osteoporosis in postmenopausal women.1 17 Risk factors for postmenopausal osteoporosis and related fractures include early menopause, advanced age, low bone mineral density (BMD), low body mass index (BMI), previous fracture or family history of fracture/osteoporosis, excessive alcohol intake, smoking, inadequate physical activity, low calcium and vitamin D intake, certain drugs (e.g., glucocorticoids), and medical conditions or diseases (e.g., rheumatoid arthritis, diabetes mellitus, Cushing syndrome, hyperparathyroidism).17 33

Treatment of osteoporosis in postmenopausal women.1 5 6 7 28 61 62

Used in men with osteoporosis to increase bone mass.1 60

In addition to adequate intake of calcium/vitamin D and other lifestyle modifications (e.g., exercise, avoidance of excessive alcohol and tobacco use), experts recommend that pharmacologic therapy for osteoporosis be considered in postmenopausal women and men (≥50 years of age) with previous hip or vertebral fractures or low BMD; pharmacologic therapy also may be considered in postmenopausal women and men (≥50 years of age) with low bone mass, although there is less evidence supporting overall fracture risk reduction in such patients.17 33

Use of a drug with proven efficacy in reducing fracture risk is recommended; bisphosphonates (e.g., alendronate, risedronate, zoledronic acid, ibandronate) are recommended as one of several first-line drugs.17 33

Individualize choice of therapy based on potential benefits (with respect to fracture risk reduction) and adverse effects of therapy, patient preferences, comorbidities, and risk factors.17 33

Has been used concomitantly with hormone replacement therapy in postmenopausal women.1 18 20

Glucocorticoid-induced Osteoporosis

Prevention and treatment of glucocorticoid-induced osteoporosis in patients initiating or already receiving therapy with glucocorticoids (at a daily dosage ≥7.5 mg of prednisone or equivalent).1 8 9 10 21 24 25 26

American College of Rheumatology (ACR) recommends optimizing calcium and vitamin D intake and lifestyle modifications (e.g., diet, smoking cessation, weight-bearing or resistance-training exercise) in all patients receiving long-term glucocorticoid therapy; in addition, pharmacologic therapy with an oral bisphosphonate is recommended in patients who are considered to be at moderate-to-high risk of fracture.622 Oral bisphosphonates generally are preferred because of their demonstrated antifracture benefits, safety, and low cost.622

Paget Disease of Bone

Treatment of Paget disease of bone (osteitis deformans).1 2 13

Risedronate Dosage and Administration

General

Oral Administration (Immediate-release Tablets)

Administer orally1 5 6 7 8 9 10 with a full glass (180–240 mL) of plain water ≥30 minutes before the first food or beverage of the day.1

Administer in an upright position (sitting or standing).1 Avoid lying down for ≥30 minutes following administration.1 (See Upper GI Effects under Cautions.)

Do not suck or chew tablets; potential for oropharyngeal irritation.1 (See Upper GI Effects under Cautions.)

Do not administer at the same time as other beverages, foods, antacids, or mineral supplements containing calcium, aluminum, or magnesium.1 5 (See Antacids or Mineral Supplements Containing Divalent Cations under Interactions.)

Missed dose in patients taking weekly 35-mg dose of risedronate sodium: take the missed dose the morning after it is remembered, then resume the regular weekly schedule.1 Do not take two 35-mg tablets on the same day.1

Missed dose in patients taking monthly 150-mg dose: If next scheduled dose is >7 days away, take the missed dose the morning after it is remembered and resume the regular schedule.1 If the next scheduled dose is 1–7 days away, maintain the regular schedule;1 do not take more than one 150-mg tablet within the same week.1

Missed dose(s) in patients taking 2 consecutive daily 75-mg doses each month and next scheduled dose is >7 days away: If one dose is missed, take the missed dose the morning after it is remembered, then resume the regular schedule.1 If both doses are missed, take one missed dose the morning after it is remembered and the next missed dose on the next consecutive morning, then resume the regular schedule.1 Do not take more than two 75-mg tablets within the same week.1

Missed dose(s) in patients taking 2 consecutive daily 75-mg doses each month and next scheduled dose is 1–7 days away: Maintain the regular schedule (i.e., wait until time of next month’s scheduled dose).1 Do not take more than two 75-mg tablets within the same week.1

Oral Administration (Delayed-release Tablets)

Administer the 35-mg delayed-release tablets in the morning immediately following breakfast; do not administer under fasting conditions to minimize risk of abdominal pain.28 Swallow tablets whole with at least 120 mL of plain water; do not chew, cut, or crush.28

Administer in an upright position (sitting or standing).28 Avoid lying down for ≥30 minutes following administration.28

Dosage

Available as risedronate sodium; dosage expressed in terms of the salt.18

Adults

Osteoporosis
Prevention of Postmenopausal Osteoporosis
Oral

5 mg once daily, 35 mg once weekly, or 150 mg monthly (given as a 150-mg tablet once monthly or a 75-mg tablet on 2 consecutive days each month).1

Treatment in Postmenopausal Women
Oral

5 mg once daily, 35 mg (given as immediate-release or delayed-release tablets) once weekly, or 150 mg monthly (given as a 150-mg tablet once monthly or a 75-mg tablet on 2 consecutive days each month).1

Optimal duration of treatment not established.1 Safety and efficacy based on data over 3 years (for immediate-release tablets) or 1 year (for 35-mg delayed-release tablets).1 28 Reevaluate need for continued therapy periodically in all patients receiving bisphosphonates.1 Consider discontinuance of bisphosphonate therapy after 3–5 years in patients at low risk of fracture.1 Evaluate fracture risk periodically in patients who discontinue therapy.1

Treatment in Men
Oral

35 mg once weekly.1

Glucocorticoid-induced Osteoporosis
Prevention
Oral

5 mg once daily.1 Safety and efficacy of use for duration >1 year not established.1

Treatment
Oral

5 mg once daily.1 Safety and efficacy of use for duration >1 year not established.1

Paget Disease of Bone
Oral

30 mg once daily for 2 months.1 2

Consider retreatment (same dosage and duration) after a 2-month posttreatment evaluation period if relapse occurs or if initial treatment failed to normalize serum alkaline phosphatase concentrations.1

Prescribing Limits

Adults

Paget Disease of Bone
Oral

Safety and efficacy not established for >1 course of retreatment.1

Special Populations

Hepatic Impairment

Dosage adjustments not necessary.1

Renal Impairment

Dosage adjustments not necessary in patients with mild to moderate impairment (Clcr ≥30 mL/minute).1 Use not recommended in patients with severe impairment (Clcr <30 mL/minute).1

Geriatric Patients

Dosage adjustments not necessary.1

Cautions for Risedronate

Contraindications

Warnings/Precautions

Formulation Considerations

Risedronate immediate-release tablets (e.g., Actonel) and risedronate delayed-release tablets (Atelvia) contain the same active ingredient; patients should not receive both formulations concomitantly.1

Upper GI Effects

Possible severe adverse esophageal effects (e.g., esophagitis, esophageal ulcers, erosions, strictures, perforation).1 (See Administration under Dosage and Administration.) Monitor for any manifestations and discontinue if dysphagia, odynophagia, new or worsening heartburn, or retrosternal pain occurs.1

Risk of severe adverse esophageal effects greater in patients who do not drink the recommended amount of water with risedronate, do not avoid lying down for ≥30 minutes following oral administration, and/or continue to take drug after developing symptoms suggesting esophageal irritation.1 Instruct patients carefully about proper administration and give copy of patient instructions provided by manufacturer.1

Use with caution in patients with active upper GI disease (e.g., Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, ulcers).1 Gastric and duodenal ulcers (some severe and with complications) reported during postmarketing experience.1

Osteonecrosis of the Jaw

Osteonecrosis and osteomyelitis of the jaw reported in patients receiving bisphosphonates.1 29 30 31 32 Mostly associated with tooth extraction and/or local infection with delayed healing.1 Known risk factors include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and comorbid disorders (e.g., periodontal and/or other preexisting dental disease, anemia, coagulopathy, infection, ill-fitting dentures).1 Risk also may increase with increased duration of bisphosphonate use.1

If osteonecrosis of the jaw develops, consult an oral surgeon for treatment.1 Dental surgery may exacerbate condition.1

In patients requiring dental procedures, discontinuance of therapy prior to procedure may reduce the risk of osteonecrosis of the jaw.1 Base management of patients requiring dental treatment on an individual assessment of risks and benefits.1

Musculoskeletal Pain

Severe and occasionally incapacitating bone, joint, and/or muscle pain reported infrequently with bisphosphonate therapy.1 35 36 Time to onset varied from 1 day to years (mean onset about 3 months) after treatment initiation.1 35 36

If severe symptoms occur, discontinue drug.35 Such pain generally improves following discontinuance of the drug, but may recur upon subsequent rechallenge with the same drug or another bisphosphonate.1 36

Atypical Fracture of the Femur

Atypical (subtrochanteric or diaphyseal), low-energy or low-trauma femur fractures reported rarely with long-term use (>3 years) of bisphosphonates, mostly in patients receiving these drugs for osteoporosis.43 44 45 Often occurs with minimal or no trauma, and may be bilateral.41 42 43 45 Causality not established; atypical fractures also occur in osteoporotic patients not receiving bisphosphonates. 43 44 45 46 Risk may be increased with concomitant use of glucocorticoid, estrogen, and proton-pump inhibitor therapy.45 47 48 50

Evaluate patients who present with new thigh or groin pain for possibility of an atypical femoral fracture; include assessment of the contralateral limb.41 42 43 45 Consider interruption of bisphosphonate therapy in patients with manifestations of possible femoral fracture; weigh risks versus benefits of continued treatment.41 42 Discontinue if a femoral shaft fracture is confirmed.43 44 45

Potential Risk of Esophageal Cancer

Some evidence (from postmarketing experience and observational studies) suggests a possible association between use of oral bisphosphonates and an increased risk of esophageal cancer.40 51 52 However, because of conflicting data,52 53 54 additional study needed to confirm such findings.51

FDA states that benefits of oral bisphosphonates continue to outweigh their potential risks in patients with osteoporosis; it is important to consider that esophageal cancer is rare, especially in women.51 52

Avoidance of oral bisphosphonates in patients with Barrett’s esophagus, a known precursor to esophageal adenocarcinoma, has been recommended.40

Metabolic Effects

Possible asymptomatic decreases in serum calcium and phosphorus concentrations.1

Correct hypocalcemia and other disturbances of bone and mineral metabolism before initiating therapy.1 If daily dietary intake is inadequate, administer supplemental calcium and vitamin D.1

Endocrine Effects

Before initiating therapy in patients receiving long-term glucocorticoid therapy, measure sex hormones and consider replacement therapy, if appropriate.1 11

Atrial Fibrillation

Although data are conflicting, possible increased risk of atrial fibrillation with use of bisphosphonates.37 38 39 FDA analysis of data from long-term (6 months to 3 years) controlled trials identified a higher rate of atrial fibrillation in patients receiving bisphosphonates (alendronate, ibandronate, risedronate, or zoledronic acid) versus placebo; however, only a few events reported in each study.39 FDA is continuing to monitor this safety concern.39

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1 Not indicated in pediatric patients.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Safety and efficacy not established.1

Renal Impairment

Decreased clearance; use not recommended in patients with severe renal impairment (Clcr <30 mL/minute).1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Postmenopausal osteoporosis: Infection (unspecified),1 back pain,1 8 10 arthralgia,1 8 10 accidental injury,1 pain (unspecified), 1 constipation,1 abdominal pain,1 5 6 8 10 urinary tract infection,1 nausea,1 diarrhea,1 dyspepsia,1 flu syndrome,1 hypertension,1 bronchitis,1 headache,1 arthritis,1 traumatic bone fracture,1 sinusitis,1 rash,1 dizziness,1 joint disorder,1 depression,1 myalgia,1 cataract,1 rhinitis,1 pharyngitis,1 increased cough.1

Paget disease: Arthralgia,1 diarrhea,1 headache,1 abdominal pain,1 rash,1 flu syndrome,1 nausea,1 peripheral edema,1 chest pain,1 constipation,1 dizziness.1

Drug Interactions

Does not induce or inhibit CYP isoenzymes and is not metabolized.1

Antacids or Mineral Supplements Containing Divalent Cations

Potential decreased risedronate absorption when administered with divalent cations (e.g., calcium, magnesium, iron).1 Do not administer these supplements and antacids at the same time as risedronate.1

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.1

Specific Drugs

Drug

Interaction

Histamine H2-receptor antagonists

No evidence of increased adverse upper GI effects1

Hormone replacement therapy

Potential additive effects on bone mineral density1 18 20

NSAIAs

No evidence of increased adverse upper GI effects1

Proton pump inhibitors

No evidence of increased adverse upper GI effects1

Risedronate Pharmacokinetics

Absorption

Bioavailability

The mean absolute oral bioavailability is 0.63%.1

Onset

Reduction of bone turnover evident within 14 days of beginning therapy; maximal effects observed in about 6 months.1

Food

When administered 30 minutes or 1 hour prior to breakfast, the extent of absorption is reduced by 55 or 30%, respectively, compared to the fasting state.1 However, drug is effective when administered ≥30 minutes before breakfast.1

Distribution

Extent

Mean steady-state volume of distribution is 6.3 L/kg.1 In animal studies, 60% of a dose distributed into bone.1

Animal data indicate that the drug crosses placenta and is distributed into fetal bones.1

Distributed into milk in animals.1 Not known whether the drug is distributed into human milk.1

Plasma Protein Binding

About 24%.1

Elimination

Metabolism

There is no evidence of systemic metabolism.1

Elimination Route

Eliminated mainly in urine; only unabsorbed drug is excreted in feces.1

Half-life

Initial half-life is about 1.5 hours and terminal exponential half-life is 480 hours.1 The terminal half-life is thought to represent the dissociation of the drug from the surface of bone.1

Special Populations

Renal clearance is decreased by 70% in patients with severe renal impairment (i.e., Clcr <30 mL/minute).1

Stability

Storage

Oral

Tablets

20–25 °C.1 28

Actions and Spectrum

Advice to Patients

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Risedronate Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg*

Actonel

Warner Chilcott

Risedronate Sodium Tablets

30 mg*

Actonel

Warner Chilcott

Risedronate Sodium Tablets

35 mg*

Actonel

Warner Chilcott

Risedronate Sodium Tablets

75 mg*

Actonel

Warner Chilcott

Risedronate Sodium Tablets

150 mg*

Actonel

Warner Chilcott

Risedronate Sodium Tablets

Tablets, delayed-release

35 mg*

Atelvia

Warner Chilcott

Risedronate Sodium Delayed-release Tablets

AHFS DI Essentials™. © Copyright 2024, Selected Revisions March 12, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

1. Warner Chilcott. Actonel (risedronate sodium) tablets prescribing information. Rockaway, NJ; 2015 April.

2. 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. http://www.ncbi.nlm.nih.gov/pubmed/10335722?dopt=AbstractPlus

5. Fogelman I, Ribot C, Smith R et al. Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2000; 85:1895-900. http://www.ncbi.nlm.nih.gov/pubmed/10843171?dopt=AbstractPlus

6. Harris ST, Watts NB, Genant HK et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA. 1999; 282:1344-52. http://www.ncbi.nlm.nih.gov/pubmed/10527181?dopt=AbstractPlus

7. Reginster J, Minne HW, Sorensen OH et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral efficacy with risedronate therapy (VERT) study group. Osteoporos Int. 2000; 11:83-91. http://www.ncbi.nlm.nih.gov/pubmed/10663363?dopt=AbstractPlus

8. Cohen S, Levy RM, Keller M et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, randomized, double-blind, placebo-controlled, parallel group study. Arthritis Rheum. 1999; 42:2309-18. http://www.ncbi.nlm.nih.gov/pubmed/10555025?dopt=AbstractPlus

9. 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. European Corticosteroid-induced osteoporosis treatment study. J Bone Miner Res. 2000; 15:1006-13. http://www.ncbi.nlm.nih.gov/pubmed/10841169?dopt=AbstractPlus

10. 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. http://www.ncbi.nlm.nih.gov/pubmed/11000340?dopt=AbstractPlus

11. Eastell R, Reid DM, Compston J et al. A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update. J Int Med. 1998; 244:271-92.

12. Lourwood DL. The pharmacology and therapeutic utility of bisphosphonates. Pharmacotherapy. 1998; 18:779-89. http://www.ncbi.nlm.nih.gov/pubmed/9692651?dopt=AbstractPlus

13. Anon. Risedronate for Paget’s disease of bone. Med Lett Drugs Ther. 1998; 40:87-8. http://www.ncbi.nlm.nih.gov/pubmed/9731243?dopt=AbstractPlus

14. Goa KL, Balfour JA. Risedronate. Drugs Aging. 1998; 13:83-91. http://www.ncbi.nlm.nih.gov/pubmed/9679211?dopt=AbstractPlus

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16. Johnston CC. Risedronate: a viewpoint. Drugs Aging. 1998; 13:92.

17. Cosman F, de Beur SJ, LeBoff MS et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014; 25:2359-81. http://www.ncbi.nlm.nih.gov/pubmed/25182228?dopt=AbstractPlus

18. Procter & Gamble Pharmaceuticals, Cincinnati, OH: Personal communication.

19. Hooper M, Ebeling P, Roberts A et al. Risedronate prevents bone loss in early postmenopausal women. Calcif Tissue Int. 1999; 64(Suppl 1):S69.

20. Harris ST, Wasnich R, Ettinger M et al. The effects of risedronate plus estrogen compared with estrogen alone in postmenopausal women. J Bone Miner Res. 1999; 14(Suppl 1):S410.

21. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum. 2001; 44:1496-503. http://www.ncbi.nlm.nih.gov/pubmed/11465699?dopt=AbstractPlus

22. Sambrook PN. Corticosteroid osteoporosis: practical implications of recent trials. J Bone Miner Res. 2000; 15:1645-9. http://www.ncbi.nlm.nih.gov/pubmed/10976984?dopt=AbstractPlus

23. Plotkin LI, Weinstein RS, Parfitt AM et al. Prevention of osteocyte and osteoblast apoptosis by biphosphonates and calcitonin. J Clin Invest. 1999; 104:1363-74. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=409837&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/10562298?dopt=AbstractPlus

24. Adachi JD, Bensen WG, Brown J et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med. 1997; 337:382-7. http://www.ncbi.nlm.nih.gov/pubmed/9241127?dopt=AbstractPlus

25. Roux C, Oriente P, Laan R et al. Randomized trial of effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. J Clin Endocrinol Metab. 1998; 83:1128-33. http://www.ncbi.nlm.nih.gov/pubmed/9543129?dopt=AbstractPlus

26. 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. http://www.ncbi.nlm.nih.gov/pubmed/11212161?dopt=AbstractPlus

27. Brown JP, Kendler DL, McClung MR et al. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int. 2002; 71:103-11. http://www.ncbi.nlm.nih.gov/pubmed/12085156?dopt=AbstractPlus

28. Warner Chilcott. Atelvia (risedronate sodium) delayed-release tablets prescribing information. Rockaway, NJ; 2015 April.

29. Ruggiero SL, Mehrotra B, Rosenberg TJ et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004; 62:527-34. http://www.ncbi.nlm.nih.gov/pubmed/15122554?dopt=AbstractPlus

30. Hohneker JA. Dear doctor letter regarding osteonecrosis of the jaw in patients with cancer receiving bisphophonates. East Hanover, NJ: Novartis; 2004 September 24.

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32. Bone HG, Santora AC. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med. 2004; 351:191-2.

33. Watts NB, Bilezikian JP, Camacho PM et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2010 Nov-Dec; 16 Suppl 3:1-37. http://www.ncbi.nlm.nih.gov/pubmed/21224201?dopt=AbstractPlus

35. Center for Drug Evaluation and Research, Food and Drug Administration. FDA Alert: Information on bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa. 2008 Jan 7. Available from FDA website. Accessed 2008 Oct 28. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm101551.htm

36. Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med. 2005; 165:346-7. http://www.ncbi.nlm.nih.gov/pubmed/15710802?dopt=AbstractPlus

37. Black DM, Delmas PD, Eastell R et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007; 356:1809-22. http://www.ncbi.nlm.nih.gov/pubmed/17476007?dopt=AbstractPlus

38. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med. 2007; 356:1895-6. http://www.ncbi.nlm.nih.gov/pubmed/17476024?dopt=AbstractPlus

39. 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. Available from FDA website. Accessed 2008 Nov 21. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136201.htm

40. Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med. 2009; 360:89-90. Letter. http://www.ncbi.nlm.nih.gov/pubmed/19118315?dopt=AbstractPlus

41. Food and Drug Administration. Actonel (risedronate sodium) tablets [2010 Oct 13: Warner Chilcott]. Safety labeling change and REMS notification. Silver Spring, MD; 2010 Oct 13. Available from FDA website. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM229231.pdf

42. Food and Drug Administration. Actonel with Calcium (risedronate and calcium carbonate) tablets [2010 Oct 13: Warner Chilcott]. Safety labeling change and REMS notification. Silver Spring, MD; 2010 (2010 Oct 13). Available from FDA website. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM229232.pdf

43. Food and Drug Administration. FDA drug safety communication: Safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. Silver Spring, MD; 2010 Oct 13. Available from FDA website. Accessed 2010 Nov 4. http://www.fda.gov/Drugs/DrugSafety/ucm229009.htm

44. Food and Drug Administration. FDA MedWatch label change: Atypical fracture update for bisphosphonates (osteoporosis drugs) including alendronate (marketed as Fosamax), alendronate with cholecalciferol (marketed as Fosamax plus D), risedronate (marketed as Actonel and Atelvia), risedronate with calcium carbonate (marketed as Actonel with Calcium), ibandronate (marketed as Boniva), and zoledronic acid (marketed as Reclast). Silver Spring, MD; 2010 Oct 13. Available from FDA website. Accessed 2010 Nov 4. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm229244.htm

45. 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. http://www.ncbi.nlm.nih.gov/pubmed/20842676?dopt=AbstractPlus

46. Food and Drug Administration. FDA News Release: Possible increased risk of thigh bone fracture with bisphosphonates. Silver Spring, MD; 2010 Oct 13. Available from FDA website. Accessed 2010 Nov 4. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229171.htm

47. Giusti A, Hamdy NA, Papapoulos SE. Atypical fractures of the femur and bisphosphonate therapy: A systematic review of case/case series studies. Bone. 2010; 47:169-80. http://www.ncbi.nlm.nih.gov/pubmed/20493982?dopt=AbstractPlus

48. Girgis CM, Sher D, Seibel MJ. Atypical femoral fractures and bisphosphonate use. N Engl J Med. 2010; 362:1848-9. http://www.ncbi.nlm.nih.gov/pubmed/20463351?dopt=AbstractPlus

49. Sellmeyer DE. Atypical fractures as a potential complication of long-term bisphosphonate therapy. JAMA. 2010; 304:1480-4. http://www.ncbi.nlm.nih.gov/pubmed/20924014?dopt=AbstractPlus

50. Schmidt GA, Horner KE, McDanel DL et al. Risks and benefits of long-term bisphosphonate therapy. Am J Health Syst Pharm. 2010; 67:994-1001. http://www.ncbi.nlm.nih.gov/pubmed/20516469?dopt=AbstractPlus

51. 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. http://www.fda.gov/Drugs/DrugSafety/ucm263320.htm

52. 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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2933354&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/20813820?dopt=AbstractPlus

53. Cardwell CR, Abnet CC, Cantwell MM et al. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA. 2010; 304:657-63. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3513370&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/20699457?dopt=AbstractPlus

54. 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.

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