Therapeutic Dimensions of Bisphosphonates: A Clinical Update

Venkataramana Vannala, Subish Palaian, Pathiyil Ravi Shankar

Abstract


Bisphosphonates (BPs) are a commonly used class of drugs for the treatment of bone disorders. An extensive review of BPs with their clinical efficacy and safety profile is unavailable. This study aimed to review the available literature on BPs, summarize their role in clinical therapy, and emphasize their safety profile. Authors reviewed the existing literature using the Google Scholar, PubMed, and Micromedex databases and analyzed the collected articles. BPs are the preferred medication for osteoporosis and other similar conditions owing to their efficient antiosteoclastic activity. Few of them are available in oral dosage forms; hence, they are patient‑friendly. The mechanism of action, common adverse effects and their clinical applications, precautions and warnings pertaining to the route of administration, and safety profiles have been discussed in this manuscript. The common adverse effects are majorly related to the gastrointestinal, cardiovascular, and endocrine system. Upon chronic usage, patients may experience serious problems like osteonecrosis of the jaw and atypical bone fractures. Although BPs are effective and safe, they may cause GI adverse effects and rare cases of osteonecrosis. Patient counseling could prove beneficial in early identification and prevention of the adverse effects associated with BPs.

Keywords


Bisphosphonates; clinical efficacy; dosage regimen; osteoporosis; safety profile; treatment outcome

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References


Aggarwal S, Gahlot N, Saini UC, Dillon MS. Bisphosphonates

in orthopedics: Evidence‑based review of indications and adverse

effects. J Postgrad Med Educ Res 2016;50:75‑85.

Widler L, Jaeggi KA, Glatt M, Müller K, Bachmann R,

Bisping M, et al. Highly potent geminal bisphosphonates. From

pamidronate disodium (Aredia) to zoledronic acid (Zometa).

J Med Chem 2002;45:3721‑38.

Grey A, Reid IR. Differences between the bisphosphonates for

the prevention and treatment of osteoporosis. Ther Clin Risk

Manag 2006;2:77.

Dunford JE, Kwaasi AA, Rogers MJ, Barnett BL, Ebetino FH,

Russell RG, et al. Structure–activity relationships among the

nitrogen containing bisphosphonates in clinical use and other

analogues: Time‑dependent inhibition of human farnesyl

pyrophosphate synthase. J Med Chem 2008;51:2187‑95.

Ziel HK, Finkle WD. Increased risk of endometrial carcinoma

among users of conjugated estrogens. N Engl J Med

;293:1167‑70.

Krishnan S, Pandian S, Kumar A. Effect of bisphosphonates

on orthodontic tooth movement‑an update. J Clin Diagn Res

;9:ZE01‑5.

Fleurence RL, Iglesias CP, Johnson JM. The cost effectiveness of

bisphosphonates for the prevention and treatment of osteoporosis.

Pharmacoeconomics 2007;25:913‑33.

Ezra A, Golomb G. Administration routes and delivery systems

of bisphosphonates for the treatment of bone resorption. Adv

Drug Deliv Rev 2000;42:175‑95.

Widler L, Jahnke W, R Green J. The chemistry of

bisphosphonates: From antiscaling agents to clinical therapeutics.

Anticancer Agents Med Chem 2012;12:95‑101.

Graham R, Russell G. The bisphosphonate odyssey. A journey

from chemistry to the clinic. Phosphorus Sulfur Silicon Relat

Elem 1999;144:793‑820.

Chemistry and classes of Bisphosphonates. Indian orthopedia

research group. Available from: http://www.iorg.co.in/2442‑2/.

[Last assessed on 2019 Aug 28].

Bisphosphonates. In: IBM Micromedex® DRUGDEX®

(electronic version). Truven Health Analytics, Greenwood

Village, Colorado, USA. Available from: http://www.

micromedexsolutions.com/. [Last cited on 2018 Jul 02].

McEvoy GK, editor. AHFS Drug Information. Bethesda:

American Society of Health System Pharmacist; 2004.

Watts NB, Bilezikian JP, Camacho PM, Greenspan SL,

Harris ST, Hodgson SF, et al. American Association of Clinical

Endocrinologists Medical Guidelines for Clinical Practice for the

diagnosis and treatment of postmenopausal osteoporosis Endocr

Pract 2010;16(Suppl 3):1‑37.

Compston J, Bowring C, Cooper A, Cooper C, Davies C,

Francis R, et al. Diagnosis and management of osteoporosis

in postmenopausal women and older men in the UK: National

Osteoporosis Guideline Group (NOGG) update 2013. Maturitas

;75:392‑6.

Management of osteoporosis in postmenopausal women: 2010

position statement of The North American Menopause Society.

Menopause 2010;17:25‑54; quiz 55‑6.

Drake MT, Clarke BL, Khosla S. Bisphosphonates: Mechanism

of action and role in clinical practice. Mayo Clin Proc

;83:1032‑45.

Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ.

Alendronate increases bone strength by increasing the mean

degree of mineralization of bone tissue in osteoporotic women.

Bone 2000;27:687‑94.

Eriksen EF, Díez‑Pérez A, Boonen S. Update on long‑term

treatment with bisphosphonates for postmenopausal osteoporosis:

A systematic review. Bone 2014;58:126‑35.

Black DM, Cummings SR, Karpf DB, Cauley JA,

Thompson DE, Nevitt MC, et al. Fracture Intervention Trial

Research Group. Randomised trial of effect of alendronate

on risk of fracture in women with existing vertebral fractures.

Lancet 1996;348:1535‑41.

Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T,

Keller M, et al. Vertebral efficacy with risedronate therapy

(VERT) study group. Effects of risedronate treatment

on vertebral and nonvertebral fractures in women with

postmenopausal osteoporosis: A randomized controlled trial.

JAMA 1999;82:1344‑52.

Gauthier K, Bai A, Perras C, Cunningham J, Ahuja T,

Richter T, et al. Denosumab, Raloxifene, and Zoledronic Acid

for the Treatment of Postmenopausal Osteoporosis: Clinical

Effectiveness and Harms. Rapid Response Report: Systematic

Review. Ottawa: Canadian Agency for Drugs and Technologies

in Health. Available from: https://www.ncbi.nlm.nih.gov/books/

NBK169524/. [Last assessed on 2019 Aug 28].

Lomer MC. Dietary and nutritional considerations for

inflammatory bowel disease. Proc Nutr Soc 2011;70:329‑35.

Gerasimidis K, McGrogan P, Edwards CA. The aetiology and

impact of malnutrition in paediatric inflammatory bowel disease.

J Hum Nutr Diet 2011;24:313‑26.

Trikudanathan G, Venkatesh PG, Navaneethan U. Diagnosis and

therapeutic management of extra‑intestinal manifestations of

inflammatory bowel disease. Drugs 2012;72:2333‑49.

Bernstein M, Irwin S, Greenberg GR. Maintenance infliximab

treatment is associated with improved bone mineral density in

Crohn’s Disease”. Am J Gastroenterol 2005;100:2031‑5.

Product Information: FOSAMAX (R) oral tablets, oral solution,

alendronate sodium oral tablets, oral solution. Merck Sharp &

Dohme Corp. (per FDA), Whitehouse Station, NJ, 2012.

Ringe JD, Dorst A, Faber H, Ibach K, Sorenson F. Intermittent

intravenous ibandronate injections reduce vertebral fracture risk

in corticosteroid induced osteoporosis: Results from a long‑term

comparative study. Osteoporos Int 2003;14:801‑7.

Krieg MA, Seydoux C, Sandini L, Goy JJ, Berguer DG, Thie D,

et al. Intravenous pamidronate as treatment for osteoporosis

after heart transplantation: A prospective study. Osteoporosis Int

;12:112‑6.

Rao SS, Budhwar N, Ashfaque A. Osteoporosis in men. Am Fam

Physician 2010;82:503‑8.

Kanis JA, Oden A, Johnell O, De Laet C, Jonsson B,

Oglesby AK. The components of excess mortality after hip

fracture. Bone 2003;32:468‑73.

Haentjens P, Magaziner J, Colón‑Emeric CS, Vanderschueren D,

Milisen K, Velkeniers B, et al. Meta‑analysis: Excess mortality

after hip fracture among older women and men. Ann Intern Med

;152:380‑90.

Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA.

Mortality after all major types of osteoporotic fracture in men

and women: An observational study. Lancet 1999;353:878‑82.

Ebeling PR. Clinical practice. Osteoporosis in men. N Engl J

Med 2008;358:1474‑82.

Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev

;29:441‑64.

Mazziotti G, Angeli A, Bilezikian JP, Canalis E,

Giustina A. Glucocorticoid‑induced osteoporosis: An update.

Trends Endocrinol Metab 2006;17:144‑9.

Angeli A, Guglielmi G, Dovio A, Capelli G, de Feo D, Giannini S,

et al. High prevalence of asymptomatic vertebral fractures in

postmenopausal women receiving chronic glucocorticoid therapy:

A cross‑sectional outpatient study. Bone 2006;39:253‑9.

Reid IR. Glucocorticoid‑induced osteoporosis: Assessment and

treatment. J Clin Densitom 1998;1:65‑73.

Maricic M, Gluck O. Densitometry in glucocorticoid‑induced

osteoporosis. J Clin Densitom 2004;7:359‑63.

Curtis JR, Westfall AO, Allison J, Becker A, Melton ME,

Freeman A, et al. Challenges in improving the quality

of osteoporosis care for long‑term glucocorticoid users:

A prospective randomized trial. Arch Intern Med 2007;167:591‑6.

de Nijs RN, Jacobs JW, Lems WF, Laan RF, Algra A,

Huisman AM, et al. STOP Investigators. Alendronate or

alfacalcidol in glucocorticoid‑induced osteoporosis. N Engl J

Med 2006;355:675‑84.

Boutsen Y, Jamart J, Esselinckx W, Stoffel M, Devogelaer JP.

Primary prevention of glucocorticoid‑induced osteoporosis with

intermittent intravenous pamidronate: A randomized trial. Calcif

Tissue Int 1997;61:266‑71.

Gilchrist NL, Frampton CM, Acland RH, Nicholls MG,

March RL, Maguire P, et al. Alendronate prevents bone loss

in patients with acute spinal cord injury: A randomized,

double‑blind, placebo‑controlled study. J Clin Endocrinol Metab

;92:1385‑90.

Nance PW, Schryvers O, Leslie W, Ludwig S, Krahn J,

Uebelhart D. Intravenous pamidronate attenuates bone density

loss after acute spinal cord. injury. Arch Phys Med Rehabil.

;80:243‑51.

Whyte MP. Paget’s disease of bone. N Engl J Med

;355:593‑600.

Ralston SH. Paget’s disease of bone. N Engl J Med

;368:644‑50.

Singer FR, Bone HG, Hosking DJ, Lyles KW, Murad MH,

Reid IR, et al. Paget’s disease of bone: An endocrine

society clinical practice guideline. J Clin Endocrinol Metab

;99:4408‑22.

Siris E, Weinstein RS, Altman R, Conte JM, Favus M,

Lombardi A, et al. Comparative study of alendronate versus

etidronate for the treatment of Paget’s disease of bone. J Clin

Endocrinol Metab 1996;81:961‑7.

Siris ES, Chines AA, Altman RD, Brown JP, Johnston CC Jr,

Lang R, et al. Risedronate in the treatment of Paget’s disease

of bone: An open label, multicenter study. J Bone Miner Res

;13:1032‑8.

Product Information: SKELID(R) oral tablets, tiludronate

disodium oral tablets. Sanofi‑Aventis U.S. LLC, Bridgewater, NJ,

Siris ES. Perspectives: A practical guide to the use of

pamidronate in the treatment of Paget’s disease. J Bone Miner

Res 1994;9:303‑4.

Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y,

et al. Comparison of a single infusion of zoledronic acid with

risedronate for Paget’s disease. N Engl J Med 2005;353:898‑908.

Green JR. Antitumour effects of bisphosphonates. Cancer

;97 (3 Suppl):840‑7.

Van Acker HH, Anguille S, Willemen Y, Smits EL,

Van Tendeloo VF. Bisphosphonates for cancer treatment:

Mechanisms of action and lessons from clinical trials. Pharmacol

Ther 2016;158:24‑40.

Green J, Czanner G, Reeves G, Watson J, Wise L, Beral V. Oral

bisphosphonates and risk of cancer of oesophagus, stomach, and

colorectum: Case–control analysis within a UK primary care

cohort. BMJ 2010;341:c4444.

Cardwell CR, Abnet CC, Cantwel MM, Murray LJ. Exposure

to oral bisphosphonates and risk of oesophageal cancer. JAMA

;304:657‑63.

Wu S, Dahut WL, Gulley JL. The use of bisphosphonates in

cancer patients. Acta Oncologica 2007;46:581‑91.

Clezardin P. The antitumor potential of bisphosphonates. Semin

Oncol 2002;29 (6 Suppl 21):33‑42.

Lee MV, Fong EM, Singer FR, Guenette RS. Bisphosphonate

inhibits the growth of prostate cancer cells. Cancer Res

;61:2602‑8.

Powles T, Paterson S, Kanis JA, McCloskey E, Ashley S, Tidy A,

et al. Randomized, placebo‑controlled trial of clodronate in patients

with primary operable breast cancer. J Clin Oncol 2002;20:3219‑24.

Gnant MF, Mlineritsch B, Luschin‑Ebengreuth G, Grampp S,

Kaessmann H, Schmid M, et al. Zoledronic acid prevents cancer

treatment‑induced bone loss in premenopausal women receiving

adjuvant endocrine therapy for hormone‑responsive breast

cancer: A report from the Austrian Breast and Colorectal Cancer

Study Group. J Clin Oncol 2007;25:820‑8.

Confavreux CB, Fontana A, Guastalla JP, Munoz F, Brun J,

Delmas PD. Estrogen‑dependent increase in bone turnover and

bone loss in postmenopausal women with breast cancer treated

with anastrozole: Prevention with bisphosphonates. Bone

;41:346‑52.

Rodan GA. Mechanisms of action of bisphosphonates. Ann Rev

Pharmacol Toxicol 1998;38:375‑88.

Oades GM, Coxon J, Colston KW. The potential role of

bisphosphonates in prostate cancer. Prostate Cancer Prostatic Dis

;5:264‑72.

Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P,

Lacombe L, et al. Zoledronic Acid Prostate Cancer Study Group.

A randomized, placebo‑controlled trial of zoledronic acid in

patients with hormone‑refractory metastatic prostate carcinoma.

J Natl Cancer Inst 2002;94:1458‑68.

Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P,

Lacombe L, et al. Long‑term efficacy of zoledronic acid

for the prevention of skeletal complications in patients with

metastatic hormone‑refractory prostate cancer. J Natl Cancer Inst

;96:879‑82.

Han SH, de Klerk JM, Tan S, van het Schip AD, Derksen BH,

van Dijk A, et al. The placorhen study: A double‑blind,

placebo‑controlled, randomized radionuclide study with

Re‑etidronate in hormone‑resistant prostate cancer patients

with painful bone metastases. J Nucl Med 2002;43:1150‑6.

Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL,

Schoenfeld DA, et al. Pamidronate to prevent bone loss during

androgen‑deprivation therapy for prostate cancer. N Engl J Med

;345:948‑55.

Michaelson MD, Kaufman DS, Lee H, McGovern FJ,

Kantoff PW, Fallon MA, et al. Randomized controlled trial

of annual zoledronic acid to prevent gonadotropin‑releasing

hormone agonist‑induced bone loss in men with prostate cancer.

J Clin Oncol 2007;25:1038‑42.

Ishizaka K, Machida T, Kobayashi S, Kanbe N, Kitahara S,

Yoshida K. Preventive effect of risedronate on bone loss in men

receiving androgendeprivation therapy for prostate cancer. Int J

Urol 2007;14:1071‑5.

Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC.

Multiple myeloma. Lancet 2009;374:324‑39.

Heusschen R, Muller J, Cithofs N, Caron F, Ceguin Y, Caers J.

Multiple myeloma bone disease: From mechanisms to next

generation therapy. Belgian J Hematol 2017;8:66‑74.

Berenson JR, Rosen LS, Howell A, Porter L, Coleman RE,

Morley W, et al. Zoledronic acid reduces skeletal-related

events in patients with osteolytic metastases: A double-blind,

randomized dose–response study. Cancer 2001;91:1191‑200.

Rosen LS, Gordon D, Kaminski M, Howell A, Belch A,

Mackey J, et al. Zoledronic acid versus pamidronate in the

treatment of skeletal metastases in patients with breast cancer or

osteolytic lesions of multiple myeloma: A phase III, double‑blind,

comparative trial. Cancer J 2001;7:377‑87.

Lacy MQ, Dispenzieri A, Gertz MA, Greipp PR, Gollbach KL,

Hayman SR, et al. Mayo Clinic consensus statement for the

use of bisphosphonates in multiple myeloma. Mayo Clin Proc

;81:1047‑53.

Osteogenesis imperfect. Genetics Home Reference. 11 October 2016.

Plotkin H. Syndromes with congenital brittle bones. BMC

Pediatr 2004;4:16.

Osteogenesis Imperfecta Overview. NIAMS. 2014 Jun. Available

from: https://www.niams.nih.gov/health‑topics/osteogenesisimperfecta. [Last assessed on 2019 Aug 28].

What Is Osteogenesis Imperfecta? Fast Facts: An Easy‑to‑Read

Series of Publications for the Public. NIAMS. 2014 Nov.

Available from: https://niamsdemo.demo6.iqsolutions.

com/health.../Osteogenesis_Imperfecta/. [Last assessed on

Aug 28].

Devogelaer JP, Malghem J, Maldague B,

Nagat de Deuxchaisnes C. Radiological manifestations of

bisphosphonate treatment with APD in a child suffering from

osteogenesis imperfecta. Skeletal Radiol 1987;16:360‑3.

Harrington J, Sochett E, Howard, A. Update on the evaluation

and treatment of osteogenesis imperfecta. Pediatr Clin North Am

;61:1243‑57.

Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate

therapy for osteogenesis imperfecta. Cochrane Database Syst

Rev 2016;10:CD005088.

Byers PH. Osteogenesis imperfecta: Perspectives and

opportunities. Pediatrics 2000;12:603‑09.

US Food and Drug Administration: Update of Safety Review

Follow‑Up to the October 1, 2007 Early Communication about

the Ongoing Safety Review of Bisphosphonates. Rockville, MD:

US Food and Drug Administration; 2008.

United States Food and Drug Administration: Early Communication

of an Ongoing Safety Review: Bisphosphonates. Rockville, MD:

United States Food and Drug Administration; 2007.

Grove EL, Abrahamsen B, Vestergaard P. Heart failure in patients

treated with bisphosphonates. J Intern Med 2013;274:342‑50.

Cummings SR, Schwartz AV, Black DM. Alendronate and atrial

fibrillation. N Engl J Med 2007;356:1895‑6.

Product Information: Aredia(R) Intravenous Injection,

Pamidronate Disodium Intravenous Injection. East Hanover, NJ:

Novartis Pharmaceuticals Corporation (per FDA); 2012.

Harinck HIJ, Papapoulos SE, Blanksma HJ, Moolenaar AJ,

Vermeij P, Bijvoet OL. Paget’s disease of bone: Early and

late responses to three different modes of treatment with

aminohydroxypropylidene biphosphonate (APD). Br Med J

;295:1301‑5.

Ralston SH, Gardner MD, Dryburgh FJ, Jenkins AS,

Cowan RA, Boyle IT. Comparison of aminohydroxypropylidene

diphosphonate, mithramycin, and corticosteroids/calcitonin

in treatment of cancer‑associated hypercalcaemia. Lancet

;2:907‑10.

Product Information: Actonel(R) Oral Tablets, Risedronate

Sodium Oral Tablets. Rockaway, NJ: Warner Chilcott (US),

LLC (per FDA); 2013.

Black DM, Delmas PD, Eastell R, Reid IR, Boonen S,

Cauley JA, et al. Once‑yearly zoledronic acid for treatment of

postmenopausal osteoporosis. N Engl J Med 2007;356:1809‑22.

Lyles KW, Colon‑Emeric CS, Magaziner JS, Adachi JD,

Pieper CF, Mautalen C, et al. HORIZON Recurrent Fracture

Trial. Zoledronic acid and clinical fractures and mortality after

hip fracture. N Engl J Med 2007;357:1799‑809.

Bundred NJ, Campbell ID, Davidson N, DeBoer RH,

Eidtmann H, Monnier A, et al. Effective inhibition of aromatase

inhibitor‑associated bone loss by zoledronic acid in postmenopausal

women with early breast cancer receiving adjuvant letrozole:

ZO‑FAST Study results. Cancer 2008;112:1001‑10.

Product Information: FOSAMAX(R) Oral Tablets, Solution,

Alendronate Sodium Oral Tablets, Solution. Whitehouse Station,

NJ: Merck Sharp & Dohme Corp (per manufacturer); 2011.

Reynolds JEF. Martindale ‑ The Extra Pharmacopeia. London:

The Pharmaceutical Press; 1991.

Pajus I, Lestang P, Liote F, Dryll A. Erythroderma after

clodronate treatment. Br Med J 1993;307:484.

Bonefos® 400mg capsules. Available from: http://www.

mhra.gov.uk/home/groups/spcpil/documents/spcpil/

con1474003403151.pdf. [Last accessed on 2018 Sep 08].

Lalinga AV, Pellegrino M, Laurini L, Miracco C. Necrobiotic

palisading granuloma at injection site of disodium clodronate:

A case report. Dermatology 1999;198:394‑5.

Product Information: Didronel(R) Oral Tablets, Etidronate

Disodium Oral Tablets. Rockaway, NJ: Warner Chilcott (US),

LLC (per Manufacturer); 2011.

Product Information: BONIVA(R) Oral Tablets, ibandronate

Sodium Oral Tablets. South San Francisco, CA: Genentech USA,

Inc. (per Manufacturer); 2015.

Risedronate sodium 35 mg film‑coated tablets. Available from:

https://mri.cts‑mrp.eu/Human/Downloads/DK_H_2019_001_

FinalPI_7of8.pdf. [Last accessed on 2018 Sep 08].

Kashyap AS, Kashyap S. Hypoparathyroidism unmasked by

alendronate. Postgrad Med 2000;76:417‑9.

Product Information: BINOSTO(R) Oral Effervescent Tablets,

Alendronate Sodium Oral Effervescent Tablets. San Antonio,

TX: Mission Pharmacal Company (per FDA); 2013.

Whitson HE, Lobaugh B, Lyles KW. Severe hypocalcemia

following bisphosphonate treatment in a patient with Paget’s

disease of bone. Bone 2006;39:954‑8.

Jones SG, Dolan G, Lengyel K, Myers B. Severe increase in

creatinine with hypocalcaemia in thalidomide‑treated myeloma

patients receiving zoledronic acid infusions. Br J Haematol

;119:576‑7.

Jacobs TP, Siris ES, Bilezikian JP, Baquiran DC, Shane E,

Canfield RE. Hypercalcemia of malignancy: Treatment with

intravenous dichloromethylene diphosphonate. Ann Intern Med

;94:312‑6.

Shane E, Jacobs TP, Siris ES, Steinberg SF, Stoddart K,

Canfield RE, et al. Therapy of hypercalcemia due to parathyroid

carcinoma with intravenous dichloromethylene diphosphonate.

Am J Med 1982;72:939‑44.

Altman RD, Johnston CC, Khairi MR, Wellman H, Serafini AN,

Sankey RR. Influence of disodium etidronate on clinical and

laboratory manifestations of Paget’s disease of bone (osteitis

deformans). N Engl J Med 1973;289:1379‑84.

BONIVA(R) Intravenous Injection, Ibandronate Intravenous

Injection. South San Francisco, CA: Genentech USA, Inc.

(per FDA); 2013.

Vitale G, Fonderico F, Martignetti A, Caraglia M, Ciccarelli A,

Nuzzo V, et al. Pamidronate improves the quality of life and

induces clinical remission of bone metastases in patients with

thyroid cancer. Br J Cancer 2001;84:1586‑90.

Product Information: ATELVIA(TM) Delayed‑Release Oral

Tablets, Risedronate Sodium Delayed‑Release Oral Tablets.

Rockaway, NJ: Warner Chilcott (US), LLC; 2010. p. 43

Alendronate (Oral route). Available from: https://www.

mayoclinic.org/drugs‑supplements/alendronate‑oral‑route/

side‑effects/drg‑20061571. [Last accessed on 2018 Sep 08].

U.S. Food and Drug Administration (FDA): FDA Drug Safety

Communication: Ongoing Safety Review Of Oral Osteoporosis

Drugs (Bisphosphonates) and Potential Increased Risk of

Esophageal Cancer. Rockville, MD: U.S. Food and Drug

Administration (FDA); 2011.

Oh YH, Yoon C, Park SM. Bisphosphonate use and

gastrointestinal tract cancer risk: Meta‑analysis of observational

studies. World J Gastroenterol 2012;18:5779‑88.

Abrahamsen B, Eiken P, Eastell R. More on reports of

esophageal cancer with oral bisphosphonate use. N Engl J Med

;360:1789, 1791‑2.

Khapra AP, Rose S. Drug injury in the upper gastrointestinal

tract: Effects of alendronate. Gastrointest Endosc Clin N Am

;16:99‑110.

Kennel KA, Drake MT. Adverse effects of bisphosphonates:

Implications for osteoporosis management. Mayo Cli Prac

;84:632‑8.

Nussbaum SR, Warrell RP Jr, Rude R, Glusman J, Bilezikian JP,

Stewart AF, et al. Dose‑response study of alendronate sodium

for the treatment of cancer‑associated hypercalcemia. J Clin

Oncol 1993;11:1618‑23.

Halabe A, Lifschitz BM, Azuri J. Liver damage due to

alendronate. N Engl J Med 2000;343:365‑6.

Goossens N, Spahr L, Rubbia‑Brandt L. Severe

immune‑mediated drug‑induced liver injury linked to

ibandronate: A case report. J Hepatol 2013;59:1139‑42.

Center for drug evaluation and research. Ibandronate Sodium.

Available from: https://www.accessdata.fda.gov/drugsatfda_docs/

nda/2008/021455Orig1s007.pdf. [Last assessed on 2019 Aug 28].

Risedronate side effects. Available from: https://www.drugs.com/

sfx/risedronate‑side‑effects.html#refs. [Last assessed on 2019

Aug 28].

Hortobbagyi Gn, Theriault RL, Lipton A, Porter L,

Blayney D, Sinoff C, et al. Long‑term prevention of skeletal

complications of metastatic breast cancer with pamidronate.

Protocol 19 Aredria Breast Cancer Study group. J Clin Oncol

;16:2038‑44.

Wysowski DK, Chang JT. Alendronate and risedronate: Reports

of severe bone, joint, and muscle pain. Arch Intern Med

;165:346‑7.

US Food and Drug Administration: Information for Healthcare

Professionals Bisphosphonates (marketed as Actonel,

Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D,

Reclast, Skelid, and Zometa). Available from: https://www.

albany.edu/sph/cphce/sta/attachment_16.pdf. [Last assessed on

Aug 28].

Lenart BA, Lorich DG, Lane JM. Atypical fractures of femoral

diaphysis in postmenopausal women taking alendronate. N Eng

J Med 2008;358:1304‑6.

Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA,

Pak CY. Severely suppressed bone turnover: A potential

complication of alendronate therapy. J Clin Endocrinol Metab

;90:1294‑301.

Park‑Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA,

Gunraj N, Austin PC, et al. Bisphosphonate use and the risk

of subtrochanteric or femoral shaft fractures in older women.

JAMA 2011;305:783‑9.

U.S. Food and Drug Administration: FDA Safety

Communication: Safety Update for Osteoporosis Drugs,

Bisphosphonates and Atypical Fractures. Rockville, MD: U.S.

Food and Drug Administration; 2010.

Orozco C, Maalouf NM. Safety of bisphosphonates. Rheum Dis

Clin North Am 2012;38:681‑705.

Marx RE. Pamidronate (Aredia) and zoledronate (Zometa)

induced avascular necrosis of the jaws: A growing epidemic.

J Oral Maxillofac Surg 2003;61:1115‑7.

Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review:

Bisphosphonates and osteonecrosis of the jaws [published

correction appears in Ann Intern Med 2006;145:235]. Ann Intern

Med 2006;144:753‑61.

Dimopoulos MA, Kastritis E, Anagnostopoulos A,

Melakopoulos I, Gika D, Moulopoulos LA, et al. Osteonecrosis

of the jaw in patients with multiple myeloma treated with

bisphosphonates: Evidence of increased risk after treatment with

zoledronic acid. Haematologica 2006;91:968‑71.

Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL.

Osteonecrosis of the jaws associated with the use of

bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg

;62:527‑34.

Coskun Benlidayi I, Guzel R. Oral bisphosphonate related

osteonecrosis of the jaw: A challenging adverse effect. ISRN

Rheumatol 2013;2013:215034. doi: 10.1155/2013/215034.

Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR,

Felsenberg D, et al. Bisphosphonate‑associated osteonecrosis

of the jaw: Report of a task force of the American Society

for Bone and Mineral Research [editorial]. J Bone Miner Res

;22:1479‑91.

Hershman DL, McMahon DJ, Crew KD, Cremers S, Irani D,

Cucchiara G, et al. Zoledronic acid prevents bone loss in

premenopausal women undergoing adjuvant chemotherapy for

early‑stage breast cancer. J Clin Oncol 2008;26:4739‑45.

Smith MR, Eastham J, Gleason DM, Shasha D,

Tchekmedyian S, Zinner N. Randomized controlled trial of

zoledronic acid to prevent bone loss in men receiving androgen

deprivation therapy for nonmetastatic prostate cancer. J Urol

;169:2008‑12.

Abu‑Id MH, Warnke PH, Gottschalk J, Springer I, Wiltfang J,

Acil Y, et al. Bis‑phossy jaws‑ High and low risk factors

for bisphosphonate‑induced osteonecrosis of the jaw.

J Craniomaxillofac Surg 2008;36:95‑103.

Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K,

de Boer RH, et al. Denosumab compared with zoledronic acid

for the treatment of bone metastases in patients with advanced

breast cancer: A randomized, double‑blind study. J Clin Oncol

;28:5132‑9.

Sim IW, Sanders KM, Borromeo GL, Seymour JF, Ebeling PR.

Declining incidence of medication‑related osteonecrosis of

the jaw in patients with cancer. J Clin Endocrinol Metab

;100:3887‑93.

Baron R, Ferrari S, Russell RG. Denosumab and

bisphosphonates: Different mechanisms of action and effects.

Bone 2011;48:677‑92.

Santini D, Vincenzi B, Dicuonzo G, Avvisati G, Massacesi C, Battistoni F, et al. Zoledronic acid induces significant and

long‑lasting modifications of circulating angiogenic factors in

cancer patients. Clin Cancer Res 2003;9:2893‑7.

Stepan JJ, Burr DB, Pavo I, Sipos A, Michalska D, Li J, et al.

Low bone mineral density is associated with bone microdamage

accumulation in postmenopausal women with osteoporosis.

Bone 2007;41:378‑85.

Ruggiero SL. Bisphosphonate‑related Osteonecrosis of the Jaws.

Compend Contin Educ Dent 2008;29:97‑105.

Product Information: BINOSTO(TM) Oral Effervescent Tablets,

Alendronate Sodium Oral Effervescent Tablets. San Antonio,

TX: Mission Pharmacal Company (per FDA); 2012.