bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday

io

REVIEW

Bisphosphonate Therapy for Osteoporosis BenefitsRisks and Drug HolidayMichael McClung MDa Steven T Harris MDb Paul D Miller MDc Douglas C Bauer MDb K Shawn Davison PhDd

Larry Dian MB BCHe David A Hanley MDf David L Kendler MDg Chui Kin Yuen MDh E Michael Lewiecki MDiaOregon Osteoporosis Center Portland bUniversity of California San Francisco cColorado Center for Bone Research LakewooddUniversity of Victoria Victoria British Columbia Canada eDivision of Geriatric Medicine University of British Columbia VancouverBritish Columbia Canada fDepartment of Medicine University of Calgary Calgary Alberta Canada gDepartment of Medicine Universityof British Columbia Vancouver British Columbia Canada hManitoba Clinic Winnipeg Manitoba Canada iNew Mexico Clinical Research

amp Osteoporosis Center Albuquerque

E-mail address

0002-9343$ -see fhttpdxdoiorg10

ABSTRACT

The amino-bisphosphonates are first-line therapy for the treatment of most patients with osteoporosis withproven efficacy to reduce fracture risk at the spine hip and other nonvertebral skeletal sites Furtherbisphosphonates have been associated with a significant decrease in morbidity and increase in survivalFollowing the use of bisphosphonates in millions of patients in clinical practice some unexpected possibleadverse effects have been reported including osteonecrosis of the jaw atypical femur fractures atrial fibrilla-tion and esophageal cancer Because bisphosphonates are incorporated into the skeleton and continue to exertan antiresorptive effect for a period of time after dosing is discontinued the concept of a drug holiday hasemerged whereby the risk of adverse effects might be decreased while the patient still benefits from antifractureefficacy Patients receiving bisphosphonates who are not at high risk for fracture are potential candidates for adrug holiday while for those with bone mineral density in the osteoporosis range or previous history of fragilityfracture the benefits of continuing therapy probably far outweigh the risk of harmcopy 2012 Elsevier Inc All rights reserved bull The American Journal of Medicine (2012) xx xxx

KEYWORDS Adverse events Bisphosphonates Drug holiday Fracture

w

Amino-bisphosphonates decrease bone resorption by inhib-iting osteoclast function1 and have proven antifracture effi-cacy in patients with osteoporosis2 At least 4 million Amer-can women were prescribed bisphosphonates to treatsteoporosis in 20083 In addition many men with osteo-

porosis and patients receiving glucocorticoids are receivingbisphosphonate therapy With such a large number of pa-tients receiving bisphosphonate therapy for ever-longer du-rations there is an increasing chorus of questions about theirlong-term use

Funding Unrestricted educational grants from Eli Lilly Warner-Chilcott Merck Novartis and Amgen were provided to the WesternOsteoporosis Alliance for the development of this manuscript The grantingcompanies had no role in the development of the manuscript or any inputas to where or if the resulting manuscript was submitted for publication

Conflict of Interest See last page of articleAuthorship See last page of articleRequests for reprints should be addressed to MR McClung Oregon

Osteoporosis Center 5050 NE Hoyt Suite 626 Portland OR 97213

mmcclungorostcom

ront matter copy 2012 Elsevier Inc All rights reserved1016jamjmed201206023

The majority of data about the fracture reduction efficacyand safety of bisphosphonates come from randomized pla-cebo-controlled phase III regulatory trials in postmeno-pausal women4-10 mostly 3 years in duration with fewerthan 50000 total subjects Some trials were extended11-13 2

ith alendronate out to 10 years1214 but clinical trial datafor long-term use of bisphosphonates are scarce with noplacebo-controlled data beyond 5 years

This commentary weighs the known antifracture benefitsof bisphosphonate therapy with their potential risks andprovides guidance as to when a bisphosphonate drug holi-day may be appropriate

LONG-TERM RETENTION OF BISPHOSPHONATEIN THE SKELETONThe effects of most therapies resolve soon after discontin-uation Bisphosphonates are unique in that they bind tohydroxyapatite in bone and can remain there for years

During remodeling which is significantly decreased by bis-

msso

e fra

ARR

ZZIAR

2 The American Journal of Medicine Vol xx No x Month 2012

phosphonate therapy some bound bisphosphonate is re-leased from bone a portion binds again to bone and ismetabolically active Skeletal binding affinity increases inrank order through risedronate ibandronate alendronateand zoledronic acid1 Bisphosphonates with higher affinityare more quickly rebound in-creasing skeletal retention

The long residence time for bis-phosphonates has potential bene-fits and risks On the positive sidediscontinuation of bisphosphonatetherapy is associated with an anti-resorptive effect and antifractureprotection that persists for an un-defined period However if ad-verse effects are associated withskeletal persistence of these drugsit might take a long time for theseto resolve

ANTIFRACTURE ANDCLINICAL EFFICACY OFBISPHOSPHONATESTable 1 provides an overview ofthe antifracture efficacy with bis-phosphonates in pivotal registra-tion trials Alendronate rise-dronate and zoledronic acid decreased fracture risk at thespine nonvertebral sites and the hip alone2 whereas iban-dronate reduced vertebral but not nonvertebral fractures15

In general the efficacy of bisphosphonates changes with thepatientrsquos primary risk profilemdashthose with the highest frac-ture risk tend to have the greatest absolute reduction in

CLINICAL SIGNIF

Protection frompersists with lonphonate theraposteoporosis

The risk of osteoatypical subtroctures with amivery small compture benefits promoderate or hig

Based on currentidayrdquo from aminot justified in phigh risk for spin

Table 1 Antifracture Benefits of Bisphosphonates for the Trea

Medication (Clinical Trial) Y

Absolute Fracture RiskReduction

Vert fx Non-vert fx H

Alendronate (FIT I)4 3 71 28 1lendronate (FIT II)5 3 17 15 0isedronate (VERT NA)6dagger 3 50 32 0isedronate (VERT MN)7dagger 3 109 51 0

Risedronate (HIP)8 3 NA 18 1oledronic acid (HORIZON PFT)9 3 76 27 1oledronic acid (HORIZON RFT)10 3 NA 31 1bandronate (BONE)15dagger 3 49 09 Nlendronate (Men)17 2 50 NA Nisedronate (GIO)18 1 110 NA N

FIT Fracture Intervention Trial GIO glucocorticoid induced ostassessed nonvert fx nonvertebral fracture VERT Vertebral Efficacy wfollow-up

Widely ranging bone mineral density age and previous fracture statutable provides a broad overview of the general benefits of the therapies inpopulations studied for each therapy please refer to the referenced pub

daggerVertebral fracture incidence rate estimated from proportional hazards mode

fracture risk Hip fracture incidence decreased between1996 and 2007 in the US when bisphosphonate use waswidespread supporting a possible benefit of bisphosphonatetherapy in reducing the risk of hip fracture16

Bisphosphonates also are approved for the treatment ofmen with osteoporosis and bothmen and women receiving gluco-corticoids based on studies dem-onstrating increases in bone min-eral density Only 2 sets of thesestudies one in men and another inpatients receiving glucocorticoidshave demonstrated reductions invertebral fracture risk with 1 yearof therapy1718

The benefits of bisphosphonatetherapy extend beyond fracture riskreduction and include a decrease inmorbidity reduced health carecosts and a significant increase insurvival19-23 Oral and intravenousbisphosphonate use for up to 3 yearswas associated with a decrease inmortality of up to 28 in patientswith recent low-trauma hip frac-tures1024 Older men and womentreated with bisphosphonates over 5years had an adjusted 27 reduc-

tion in risk of death compared with nonusers21 In a recenteta-analysis the use of osteoporosis therapies including bi-

phosphonates for more than 1 year was associated with aignificant decrease in mortality in older patients at a high riskf fracture25

CE

ortant fracturesm amino-bisphos-

patients with

sis of the jaw andric femoral frac-sphosphonates iswith the antifrac-

in individuals atture risk

ence a ldquodrug hol-sphosphonates ists who remain atcture

of Postmenopausal Osteoporosis

Relative Fracture RiskReduction

Number Needed to Treat toPrevent One Fracture

Vert fx Non-vert fx Hip fx Vert fx Non-vert fx Hip fx

471 189 508 14 36 90443 111 207 60 68 447307 381 197 20 31 276376 319 182 9 20 203

NA 161 282 NA 56 91700 252 440 13 37 91

NA 290 429 NA 32 6762 11 NA 20 NA NA62 NA NA 9 NA NA70 NA NA 9 NA NA

sis HIP Hip Intervention Program hip fx hip fracture NA notdronate Therapy study vert fx vertebral fracture Y average years of

study populations make direct comparisons of therapies impossible Thisective clinical trial population For more information about the particular

ICAN

impg-tery in

necrohanteno-biaredvided

h frac

evidno-biatien

tment

ip fx

1

2

4

5

1

1

5AAA

eoporoith Rise

s in thethe resplication

ls

trumprcTsb

vtldquodepsro

afotaeopaf

1ctid18rn

fyrthtap

3McClung et al Bisphosphonate Risks and Drug Holidays

RISKS ASSOCIATED WITH BISPHOSPHONATETHERAPYThe overall frequency of adverse events (any undesirablemedical occurrence associated with the use of a medicalproduct in a patient irrespective of causality)26 or seriousadverse events (life-threatening resulting in death hospi-talization prolongation of hospitalization significant dis-ability or birth defect) did not differ between groups re-ceiving bisphosphonates or placebo in pivotal clinical trialsAdverse events and serious adverse events that are attribut-able (ie causally related) to the therapy (ldquoside effectsrdquo in layterms) may be identified in placebo-controlled trials if theyare relatively common Rare treatment-related complica-tions may only come to attention after many thousands ifnot millions of patients are exposed to a drug in the ldquorealworldrdquo clinical setting Additionally patients treated clini-cally often have conditions (eg comorbidities other medi-cations advanced age impaired renal function) that mightpredispose them to undesirable medical occurrences notseen in healthier clinical trial subjects27 While the overallrates of serious adverse events reported in bisphosphonateclinical trials were low highly publicized postmarketing re-ports have linked bisphosphonates to undesirable medical oc-currences including osteonecrosis of the jaw atypical femurfracture atrial fibrillation and esophageal cancer

OSTEONECROSIS OF THE JAWBisphosphonate-associated osteonecrosis of the jaw (ex-posed bone in the maxillofacial region with no healingwithin 8 weeks in a patient with bisphosphonate exposureand no history of craniofacial radiation therapy) is mostoften observed (95 of cases) after invasive dental proce-dures during oncology therapy with high doses of intrave-nous bisphosphonates delivered frequently to an immuno-suppressed population28 The incidence of osteonecrosis ofhe jaw in patients receiving bisphosphonates for osteopo-osis or the healthy adult population is unknown In chronicsers of oral bisphosphonate therapy for osteoporosis esti-ates of that risk range between 1 in 1000 and 1 in 263000

atient-years with minimal evidence for an association ofisk with duration of therapy28-35 Poor oral hygiene glu-ocorticoid therapy and chemotherapy may be risk factorshis problem also occurs in patients unexposed to bispho-phonates and causality between this disorder and oralisphosphonate use has not been established

Due to lack of evidence there is uncertainty about thealue of withholding bisphosphonates before invasive den-al surgery The American Dental Association suggests thatthe decision to discontinue therapy should be a medicalecision based primarily upon the risk for skeletally relatedvents (eg fractures) secondary to low bone density not theotential risk of osteonecrosis of the jawrdquo36 The use oferum C-telopeptide of Type I collagen a marker of boneesorption to assess the risk of jaw osteonecrosis in patientsn bisphosphonates has been recommended37 but because

of the paucity of evidence supporting this approach the use t

of serum C-telopeptide of Type I collagen is not endorsedby the American Dental Association In patients with os-teoporosis the benefit of bisphosphonates in reducing frac-ture risk far outweighs the remote potential risk of osteo-necrosis of the jaw

ATYPICAL FEMUR FRACTURESA consensus document defined the major features of anatypical femoral fracture (located in the subtrochantericregion and femoral shaft transverse or short oblique orien-tation occurring spontaneously or after minimal traumapossessing a medial spike absence of comminution) dis-tinguishing these fractures from the more common rdquotypicalrdquofemoral shaft fracture that is a complication of osteoporo-sis38 Glucocorticoids and proton-pump inhibitor therapyhave been identified as risk factors for atypical fractures insome39 but not all4041 studies Atypical femoral fractureslso occur in bisphosphonate-naiumlve patients41-46 Sparse in-ormation is available about the incidence of atypical fem-ral fractures in patients with and without bisphosphonatereatment Estimates of risk are inconsistent but the riskppears to rise with increased duration of bisphosphonatexposure404647 A retrospective analysis of 15000 fem-ral fractures in an American population identified 142atients with radiographically confirmed fractures withtypical features 128 of whom had taken a bisphosphonateor an average of 55 years47 Risk increased from 178

atypical femoral fractures per 100000 patientyears treatedfor 2 years to 1131 such fractures per 100000 patientyearswith treatment for 8-10 years In a Swedish national popu-lation survey of 12000 femur fractures (including about1000 hip fractures) 59 radiographically confirmed atypi-al femoral fractures occurred of which 78 were in pa-ients with a history of bisphosphonate use40 The differencen atypical femoral fracture risk between patients who did orid not take bisphosphonates was 18 atypical fractures per0000 patientsyear for up to 2 years of treatment and410000 patientsyear with use of more than 2 years Theisk diminished substantially and rapidly after bisphospho-ate discontinuation

These results suggest that the absolute risk of atypicalracture associated with bisphosphonate use even beyond 5ears is small for the individual osteoporosis patient at highisk of fractures compared with the beneficial effects ofreatment Consistent with this was an analysis of 90 millionospital discharge records (1996-2007) which suggestedhat for every subtrochanteric fracture (typical and atypical)ssociated with bisphosphonate use 100 hip fractures wererevented in addition to prevention of other fractures16

ATRIAL FIBRILLATIONAn increased incidence of atrial fibrillation as a seriousadverse event was reported in the pivotal phase III trial ofannual intravenous zoledronic acid (13 in the treatedgroup 05 in the placebo group P 001)9 although

here were no differences between groups in total cases of

vcc

sw

t

buptnp

hr

tfcsydrcr


atrial fibrillation or other cardiovascular events While car-diac abnormalities could be the result of a transient decreasein serum calcium the serious adverse events were not clus-tered at the beginning of the therapy or at the time of theannual doses In analyses of other large clinical trials(mostly post hoc) there were no associations between atrialfibrillation and bisphosphonate treatment1048-50 After a re-iew of these data the US Food and Drug Administrationoncluded that concerns about atrial fibrillation need not beonsidered in decisions about therapy for osteoporosis51

ESOPHAGEAL CANCERSeveral cases of esophageal cancer occurring in patientswith a history of oral bisphosphonate use have been re-ported52 While one large case-control analysis reported aignificant increase in the incidence of esophageal cancerith long-term oral bisphosphonate use53 other reports

found no significant increases54-56 The US Food and DrugAdministration has determined that at this time there is notenough information to make definitive conclusions about apossible association between oral bisphosphonates andesophageal cancer57

OTHER RISKS AND CONCERNS

Gastrointestinal IntoleranceAlthough not observed in clinical trials gastrointestinalintolerance esophageal irritation or erosion have been re-ported with oral bisphosphonate use especially if takenincorrectly6-858-63 Isolated cases of serious esophagealcomplications or upper gastrointestinal hemorrhage haveoccurred64 Oral bisphosphonates are contraindicated in pa-ients with impaired swallowing

Impairment of Renal FunctionBisphosphonates can be nephrotoxic when high doses areadministered rapidly6566 Impaired renal function has noteen observed in clinical trials when bisphosphonates aresed according to prescribing instructions in well-hydratedatients but postmarketing cases of renal failure after in-ravenous zoledronic acid have been reported Bisphospho-ate therapy is not recommended or is contraindicated inatients with significantly impaired renal function67

Flu-like SymptomsAcute phase reactions with transient mild to moderate in-fluenza-like symptoms occur with monthly oral6869 or in-travenous bisphosphonate therapy9107071

HypocalcemiaBy inhibiting bone resorption bisphosphonates reduce cal-cium efflux from bone resulting in a small transient de-crease in serum calcium7273 Risk factors for symptomaticypocalcemia include vitamin D deficiency hypoparathy-

oidism and impaired renal function

Impaired Fracture HealingTo date there is no clinical evidence that bisphosphonatetherapy impairs fracture healing

Inflammatory Eye DisordersVery rare cases of inflammatory eye disorders have beendescribed with oral and intravenous bisphosphonateuse7475

BISPHOSPHONATE ldquoDRUG HOLIDAYrdquoIt is unusual to contemplate a drug holiday in the treatmentof most chronic diseases because with most therapies ben-eficial drug effects rapidly diminish with discontinuationHowever the long skeletal residence time of bisphospho-nates and concern about the risks of rare adverse events withlong-term therapy raise the possibility that bisphosphonatetherapy may be interrupted for a ldquodrug holidayrdquo duringwhich antifracture benefit might persist for a period of timewhile potential risks are minimized76 Intuitively upon bis-phosphonate discontinuation both the potential benefit andrisks of the residual bisphosphonate effect would decreaseover time as the drug is gradually removed from theskeleton

In assessing the potential utility of a drug holiday itwould be ideal to have clinical trial data comparing fracturerisk between patients who continue or stop therapy unfor-tunately only 3 prospective studies have addressed thisissue127778 In patients treated with annual zoledronic acidfor 3 years treatment for 3 additional years resulted in a52 lower risk of morphometric vertebral fracture com-pared with treatment for 3 years followed by placebo for thenext 3 years (fracture rates 30 vs 62 respectively)77

The risks of other fracturesmdashincluding clinical or symp-tomatic vertebral fracturesmdashdid not differ between groupsThe Fracture Intervention Trial Long-term Extension trialrandomized patients completing 5 years of alendronate ther-apy to 5 additional years of alendronate or placebo12 Al-though the subject number was small those continuingalendronate for 10 years had fewer clinical vertebral frac-tures than the subjects receiving the drug for only 5 years(53 vs 24 respectively) There was no difference be-tween groups for morphometric vertebral or nonvertebralfractures A post hoc analysis of the Fracture InterventionTrial Long-term Extension trial patients at high risk (T-score of 25 but without prevalent vertebral fracture) athe time of discontinuation demonstrated an increased riskor all clinical fractures associated with a discontinuationompared with remaining on alendronate therapy79 In amall study of patients given risedronate or placebo for 3ears who were then followed for an additional year afteriscontinuation morphometric vertebral fracture incidenceemained 46 lower in the former risedronate group asompared with the former placebo group (65 vs 116espectively)78 However there was no group of patients

continuing on risedronate so it was not possible to compare

fracture risk of discontinuing therapy with continuing ther-

tsmpu

ehmttdtnr


apy There is no information about fracture risk upon dis-continuing ibandronate therapy Increased risk of fractureupon discontinuing bisphosphonates compared with con-tinuing therapy also has been observed in analyses of largehealth care databases8081

It would be helpful to have clinical trials comparing ratesof adverse and serious adverse experiences in subjects ran-domized to continuing or discontinuing bisphosphonatetherapy Logically if rare undesirable medical occurrencesare causally related to bisphosphonate use the risk shoulddiminish over time as the bisphosphonate is eliminated frombone However apart from the Swedish data suggesting thatthe risk of atypical femoral fractures decreases followingdiscontinuation of oral bisphosphonate40 there are no datato answer this question

These data suggest that after bisphosphonate exposureof 3-5 years in postmenopausal women with osteoporosisprotection from fractures persists for an unknown interval oftime when therapy is withdrawn that this protection waneswithin 3-5 years of discontinuation and that the risk of atypicalfemoral fractures increases with duration of therapy but maydecrease upon withdrawal of treatment There are currently nodata about the effects of withdrawing therapy in men or pa-tients receiving glucocorticoids While there is little reason tothink that the response to withdrawing treatment woulddiffer between men and postmenopausal women it is un-certain what the bone mineral density or fracture response tostopping therapy would be in glucocorticoid-inducedosteoporosis

There are limited data to guide decision-making aboutthe initiation and termination of ldquodrug holidaysrdquo Treatmentdecisions should be individualized according to a consider-ation of all available clinical information In the absence ofclear evidence any recommendations for initiating a drugholiday or how then to monitor patients can only be ldquoexpertopinionrdquo

Our recommendations for considering a drug holiday are

Table 2 Recommendations for Drug Holiday from Bisphosphon

Patient Category Recommendation

High-riskT-score still 25 at the hipprevious fracture of the hip or spineor ongoing high-dose glucocorticoidtherapy

Drug holiday not

Moderate riskHip bone mineral density value isnow 25 (T-score) and no priorhip or spine fracture

Consider drug hoalendronate rzoledronic aci

No information adrug holidays

Low riskDid not meet current treatmentcriteria at the time of treatmentinitiation

Discontinue ther

presented in Table 2 The decision to stop or to continue

therapy must be individualized based upon an assessment ofthe patientrsquos current fracture risk These recommendationsare in accord with the proposals made by the US Food andDrug Administration about the duration of bisphosphonatetherapy that became available after our paper was submittedfor publication82 A drug holiday should be viewed as aemporary not permanent suspension of active therapy Ithould be remembered that discontinuing a bisphosphonateay not necessarily be a ldquoholidayrdquo from treatment because

ersistence of the antiresorptive effect is expected for anndefined period of time

MONITORING A DRUG HOLIDAYThere are no data providing information on how to monitorpatients or when to restart therapy after a holiday In trialswith women who had previously been provided alendronateor zoledronic acid women were followed for 5 and 3 yearsrespectively after discontinuation of therapy during whichvertebral fracture risk increased in those who stopped thedrug1277 In the absence of guidance from clinical trialsmpiric approaches are necessary Although the approachas not been studied bone mineral density and biochemicalarkers of bone turnover measured 2-3 years after discon-

inuation may provide information about the persistence ofhe effect of the retained bisphosphonate A significantecrease in bone density or a significant increase in boneurnover marker suggests that the benefits of bisphospho-ate therapy may be diminishing and that it may be time toeturn to active therapy83 Another untested approach is to

reevaluate the patient 2-3 years after discontinuation mak-ing the decisions to restart therapy based on an updatedassessment of fracture risk using algorithms initially devel-oped for untreated individuals For example if the patienthas a T-score 25 or if the patient has a T-score between10 and 25 and a World Health Organizationrsquos FractureRisk Assessment estimate of fracture risk that meets treat-

Comment

ed Re-assess the need for therapy atregular intervals

fter 3-5 years ofate orpybandronate and

These patients should not be forced totake a drug holidaymdashdecisionshould be an individual informedchoice with discussion of thepotential benefits and risks

Re-start when indications for therapyare met

ates

justifi

liday aisedrond therabout i

apy

ment guidelines consider reinitiating therapy If at any

pttyfBjt

tioot


time during the drug holiday there is a fracture restartingtherapy (not necessarily a bisphosphonate) is advised Moreresearch is needed about the role of serial bone densitytesting and bone turnover markers in monitoring fracturerisk after therapy cessation as well as the optimal therapiesto use following a drug holiday

WEIGHING THE BENEFITS AND THE RISKSWhen all of the evidence is considered the antifracturebenefit provided by the amino-bisphosphonates far out-weighs the potential risks of therapy in most patients at highrisk of fracture Depending on the severity of osteoporosisbetween 9 and 60 patients need to be treated for 3 years toprevent one vertebral fracture (Table 1) between 20 and 68atients need to be treated for 3 years to avoid one nonver-ebral fracture Even discounting the increased risk of frac-ure with advancing age the number needed to treat for 8ears would be between 3 and 23 to prevent a vertebralracture and between 7 and 26 for nonvertebral fractureased on the range of risk estimates for osteonecrosis of the

aw one case would occur for every 1000 to 100000 pa-ients treated Using the data from California47 one atypical

femoral fracture would occur in 1282 patients treated for 8years Based on the Swedish data40 8 years of therapywould result in one atypical femoral fracture for every 149patients treated (84 cases10000 patient-years)

These estimates of benefits and risks come from studiesgenerally involving healthy older Caucasian postmeno-pausal women with osteoporosis and may not pertain toother patients including younger women other races pa-tients at low fracture risk and those with other medicalproblems or who take medications such as glucocorticoidsor chemotherapy

Careful attention must be taken to ensure that patientsprescribed bisphosphonate therapy are likely to benefit TheWorld Health Organizationrsquos Fracture Risk Assessmenttool84 and similar Canadian Association of RadiologyndashOs-eoporosis Canada Fracture Assessment tool85 can helpdentify those patients at moderate-to-high risk for whomsteoporosis treatment is appropriate In patients at low riskf fracture the balance between benefit and risk makesreatment less attractive

References1 Russell RG Watts NB Ebetino FH Rogers MJ Mechanisms of action

of bisphosphonates similarities and differences and their potentialinfluence on clinical efficacy Osteoporos Int 200819733-759

2 MacLean C Newberry S Maglione M et al Systematic reviewcomparative effectiveness of treatments to prevent fractures in menand women with low bone density or osteoporosis Ann Intern Med2008148197-213

3 Siris ES Pasquale MK Wang Y Watts NB Estimating bisphospho-nate use and fracture reduction among US women aged 45 years andolder 2001-2008 J Bone Miner Res 2011263-11

4 Black DM Cummings SR Karpf DB et al Randomised trial of effectof alendronate on risk of fracture in women with existing vertebralfractures Fracture Intervention Trial Research Group Lancet 1996

3481535-1541

5 Cummings SR Black DM Thompson DE et al Effect of alendronateon risk of fracture in women with low bone density but withoutvertebral fractures results from the Fracture Intervention Trial JAMA19982802077-2082

6 Harris ST Watts NB Genant HK et al Effects of risedronate treat-ment on vertebral and nonvertebral fractures in women with postmeno-pausal osteoporosis a randomized controlled trial Vertebral EfficacyWith Risedronate Therapy (VERT) Study Group JAMA 19992821344-1352

7 Reginster J Minne HW Sorensen OH et al Randomized trial of theeffects of risedronate on vertebral fractures in women with establishedpostmenopausal osteoporosis Vertebral Efficacy with RisedronateTherapy (VERT) Study Group Osteoporos Int 20001183-91

8 McClung MR Geusens P Miller PD et al Effect of risedronate on therisk of hip fracture in elderly women Hip Intervention Program StudyGroup N Engl J Med 2001344333-340

9 Black DM Delmas PD Eastell R et al Once-yearly zoledronic acidfor treatment of postmenopausal osteoporosis N Engl J Med 20073561809-1822

10 Lyles KW Colon-Emeric CS Magaziner JS et al Zoledronic acid andclinical fractures and mortality after hip fracture N Engl J Med20073571799-1809

11 Ensrud KE Barrett-Connor EL Schwartz A et al Randomized trial ofeffect of alendronate continuation versus discontinuation in womenwith low BMD results from the Fracture Intervention Trial long-termextension J Bone Miner Res 2004191259-1269

12 Black DM Schwartz AV Ensrud KE et al Effects of continuing orstopping alendronate after 5 years of treatment the Fracture Interven-tion Trial Long-term Extension (FLEX) a randomized trial JAMA20062962927-2938

13 Mellstrom DD Sorensen OH Goemaere S Roux C Johnson TDChines AA Seven years of treatment with risedronate in women withpostmenopausal osteoporosis Calcif Tissue Int 200475462-468

14 Bone HG Hosking D Devogelaer JP et al Ten yearsrsquo experience withalendronate for osteoporosis in postmenopausal women N Engl J Med20043501189-1199

15 Chesnut CH III Skag A Christiansen C et al Effects of oral iban-dronate administered daily or intermittently on fracture risk in post-menopausal osteoporosis J Bone Miner Res 2004191241-1249

16 Wang Z Bhattacharyya T Trends in incidence of subtrochantericfragility fractures and bisphosphonate use among the US elderly1996-2007 J Bone Miner Res 201126553-560

17 Orwoll E Ettinger M Weiss S et al Alendronate for the treatment ofosteoporosis in men N Engl J Med 2000343604-610

18 Wallach S Cohen S Reid DM et al Effects of risedronate treatmenton bone density and vertebral fracture in patients on corticosteroidtherapy Calcif Tissue Int 200067277-285

19 Nevitt MC Thompson DE Black DM et al Effect of alendronate onlimited-activity days and bed-disability days caused by back pain inpostmenopausal women with existing vertebral fractures FractureIntervention Trial Research Group Arch Intern Med 200016077-85

20 Center JR Bliuc D Nguyen ND Nguyen TV Eisman JA Osteopo-rosis medication and reduced mortality risk in elderly women and menJ Clin Endocrinol Metab 2011961006-1014

21 Sambrook PN Cameron ID Chen JS et al Oral bisphosphonates areassociated with reduced mortality in frail older people a prospectivefive-year study Osteoporos Int 2011222551-2556

22 Dell R Greene D Is osteoporosis disease management cost effectiveCurr Osteoporos Rep 2010849-55

23 Newman ED Ayoub WT Starkey RH Diehl JM Wood GC Osteo-porosis disease management in a rural health care population hipfracture reduction and reduced costs in postmenopausal women after 5years Osteoporos Int 200314146-151

24 Beaupre LA Morrish DW Hanley DA et al Oral bisphosphonates areassociated with reduced mortality after hip fracture Osteoporos Int

201122983-991

2

2

2

2

3

3

3

3

3

3

3

3

3

3

4

4

4

4

4

4


25 Bolland MJ Grey AB Gamble GD Reid IR Effect of osteoporosistreatment on mortality a meta-analysis J Clin Endocrinol Metab2010951174-1181

6 US Food and Drug Administration What is a serious adverse eventAvailable at httpwwwfda govsafetymedwatchhowtoreportucm053087htm Accessed October 31 2011

7 Dowd R Recker RR Heaney RP Study subjects and ordinary patientsOsteoporos Int 200011533-536

8 Khosla S Burr D Cauley J et al Bisphosphonate-associated osteo-necrosis of the jaw report of a task force of the American Society forBone and Mineral Research J Bone Miner Res 2007221479-1491

9 Migliorati CA Schubert MM Peterson DE Seneda LM Bisphospho-nate-associated osteonecrosis of mandibular and maxillary bone anemerging oral complication of supportive cancer therapy Cancer200510483-93

0 Ruggiero SL Mehrotra B Rosenberg TJ Engroff SL Osteonecrosis ofthe jaws associated with the use of bisphosphonates a review of 63cases J Oral Maxillofac Surg 200462527-534

1 Sarathy AP Bourgeois SL Jr Goodell GG Bisphosphonate-associatedosteonecrosis of the jaws and endodontic treatment two case reportsJ Endod 200531759-763

2 Olson KB Hellie CM Pienta KJ Osteonecrosis of jaw in patient withhormone-refractory prostate cancer treated with zoledronic acid Urol-ogy 200566658

3 Cartsos VM Zhu S Zavras AI Bisphosphonate use and the risk ofadverse jaw outcomes a medical claims study of 714217 people J AmDent Assoc 200813923-30

4 Lo JC OrsquoRyan FS Gordon NP et al Prevalence of osteonecrosis ofthe jaw in patients with oral bisphosphonate exposure J Oral Maxil-lofac Surg 201068243-253

5 Mavrokokki T Cheng A Stein B Goss A Nature and frequency ofbisphosphonate-associated osteonecrosis of the jaws in AustraliaJ Oral Maxillofac Surg 200765415-423

6 Hellstein JW Adler RA Edwards B et al Managing the care ofpatients receiving antiresorptive therapy for prevention and treatmentof osteoporosis executive summary of recommendations from theAmerican Dental Association Council on Scientific Affairs J Am DentAssoc 20111421243-1251

7 Marx RE Cillo JE Jr Ulloa JJ Oral bisphosphonate-induced osteo-necrosis risk factors prediction of risk using serum CTX testingprevention and treatment J Oral Maxillofac Surg 2007652397-2410

8 Shane E Burr D Ebeling PR et al Atypical subtrochanteric anddiaphyseal femoral fractures report of a task force of the AmericanSociety for Bone and Mineral Research J Bone Miner Res 2010252267-2294

9 Giusti A Hamdy NA Papapoulos SE Atypical fractures of the femurand bisphosphonate therapy a systematic review of casecase seriesstudies Bone 201047(2)169-180

0 Schilcher J Michaelsson K Aspenberg P Bisphosphonate use andatypical fractures of the femoral shaft N Engl J Med 20113641728-1737

1 Feldstein A Black D Perrin N et al Incidence and demography offemur fractures with and without atypical features J Bone Miner Res201227(5)977-986

2 Kumm DA Rack C Rutt J Subtrochanteric stress fracture of thefemur following total knee arthroplasty J Arthroplasty 199712580-583

3 Niimi R Hasegawa M Sudo A Uchida A Unilateral stress fracture ofthe femoral shaft combined with contralateral insufficiency fracture ofthe femoral shaft after bilateral total knee arthroplasty J Orthop Sci200813572-575

4 Lenart BA Neviaser AS Lyman S et al Association of low-energyfemoral fractures with prolonged bisphosphonate use a case controlstudy Osteoporos Int 2009201353-1362

5 Schilcher J Aspenberg P Incidence of stress fractures of the femoralshaft in women treated with bisphosphonate Acta Orthop 200980

413-415

46 Giusti A Hamdy NA Dekkers OM Ramautar SR Dijkstra S Papa-poulos SE Atypical fractures and bisphosphonate therapy a cohortstudy of patients with femoral fracture with radiographic adjudicationof fracture site and features Bone 201148966-971

47 Dell RM Adams AL Greene DF et al Incidence of atypical nontrau-matic diaphyseal fractures of the femur J Bone Miner Res 2012 Jul26 doi 101002jbmr1719 [Epub ahead of print]

48 Cummings SR Schwartz AV Black DM Alendronate and atrialfibrillation N Engl J Med 20073561895-1896

49 Karam R Camm J McClung M Yearly zoledronic acid in postmeno-pausal osteoporosis N Engl J Med 2007357712-713

50 Lewiecki EM Cooper C Thompson E Hartl F Mehta D PapapoulosSE Ibandronate does not increase risk of atrial fibrillation in analysisof pivotal clinical trials Int J Clin Pract 201064821-826

51 US Food and Drug Administration Update of safety review fol-low-up to the October 1 2007 Early communication about theongoing safety review of bisphosphonates Available at httpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersDrugSafetyInformationforHeathcareProfessionalsucm136201 Accessed August 11 2011

52 Wysowski DK Reports of esophageal cancer with oral bisphosphonateuse N Engl J Med 200936089-90

53 Green J Czanner G Reeves G Watson J Wise L Beral V Oralbisphosphonates and risk of cancer of oesophagus stomach and colo-rectum case-control analysis within a UK primary care cohort BMJ2010341c4444

54 Abrahamsen B Eiken P Eastell R More on reports of esophagealcancer with oral bisphosphonate use N Engl J Med 20093601789author reply 1791-1792

55 Solomon DH Patrick A Brookhart MA More on reports of esopha-geal cancer with oral bisphosphonate use N Engl J Med 20093601789-1790

56 Cardwell CR Abnet CC Cantwell MM Murray LJ Exposure to oralbisphosphonates and risk of esophageal cancer JAMA 2010 August11304657-663

57 US Food and Drug Administration FDA drug safety communicationongoing safety review of oral osteoporosis drugs (bisphosphonates)and potential increased risk of esophageal cancer Available at httpwwwfdagovDrugsDrugSafetyucm263320htm Accessed January12 2012

58 Cryer B Bauer DC Oral bisphosphonates and upper gastrointestinaltract problems what is the evidence Mayo Clin Proc 2002771031-1043

59 Greenspan S Field-Munves E Tonino R et al Tolerability of once-weekly alendronate in patients with osteoporosis a randomized dou-ble-blind placebo-controlled study Mayo Clin Proc 2002771044-1052

60 Miller PD Epstein S Sedarati F Reginster JY Once-monthly oralibandronate compared with weekly oral alendronate in postmeno-pausal osteoporosis results from the head-to-head MOTION studyCurr Med Res Opin 200824207-213

61 Harris ST Reginster JY Harley C et al Risk of fracture in womentreated with monthly oral ibandronate or weekly bisphosphonates theeValuation of IBandronate Efficacy (VIBE) database fracture studyBone 200944758-765

62 de Groen PC Lubbe DF Hirsch LJ et al Esophagitis associated withthe use of alendronate N Engl J Med 19963351016-1021

63 Strampel W Emkey R Civitelli R Safety considerations with bisphos-phonates for the treatment of osteoporosis Drug Saf 200730755-763

64 Cadarette SM Katz JN Brookhart MA et al Comparative gastroin-testinal safety of weekly oral bisphosphonates Osteoporos Int 2009201735-1747

65 Body JJ Pfister T Bauss F Preclinical perspectives on bisphosphonaterenal safety Oncologist 200510(Suppl 1)3-7

66 Markowitz GS Fine PL Stack JI et al Toxic acute tubular necrosisfollowing treatment with zoledronate (Zometa) Kidney Int 200364

281-289

6

7

7

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67 US Food and Drug Administration FDA drug safety communicationnew contraindication and updated warning on kidney impairment forReclast (zoledronic acid) Available at httpwwwfdagovDrugsDrugSafetyucm270199htm Accessed February 9 2012

68 Miller PD McClung MR Macovei L et al Monthly oral ibandronatetherapy in postmenopausal osteoporosis 1-year results from the MO-BILE study J Bone Miner Res 2005201315-1322

9 Bock O Boerst H Thomasius FE et al Common musculoskeletaladverse effects of oral treatment with once weekly alendronate andrisedronate in patients with osteoporosis and ways for their preventionJ Musculoskelet Neuronal Interact 20077144-148

0 Delmas PD Adami S Strugala C et al Intravenous ibandronateinjections in postmenopausal women with osteoporosis one-year re-sults from the dosing intravenous administration study ArthritisRheum 2006541838-1846

1 Reid IR Gamble GD Mesenbrink P Lakatos P Black DM Charac-terization of and risk factors for the acute-phase response after zole-dronic acid J Clin Endocrinol Metab 2010954380-4387

2 Chesnut CH III McClung MR Ensrud KE et al Alendronate treat-ment of the postmenopausal osteoporotic woman effect of multipledosages on bone mass and bone remodeling Am J Med 199599144-152

73 Papapoulos SE Harinck HI Bijvoet OL Gleed JH Fraher LJ OrsquoRiordanJL Effects of decreasing serum calcium on circulating parathyroid hor-mone and vitamin D metabolites in normocalcaemic and hypercalcaemicpatients treated with APD Bone Miner 1986169-78

74 Sharma NS Ooi JL Masselos K Hooper MJ Francis IC Zoledronicacid infusion and orbital inflammatory disease N Engl J Med 20083591410-1411

75 Fraunfelder FW Ocular side effects associated with bisphosphonatesDrugs Today (Barc) 200339829-835

76 Bonnick SL Going on a drug holiday J Clin Densitom 201114377-383

77 Black DM Reid IR Boonen S et al The effect of 3 versus 6 years ofzoledronic acid treatment of osteoporosis a randomized extension tothe HORIZON-Pivotal Fracture Trial (PFT) J Bone Miner Res 201227(2)243-254

78 Watts NB Chines A Olszynski WP et al Fracture risk remainsreduced one year after discontinuation of risedronate Osteoporos Int200819365-372

79 Schwartz AV Bauer DC Cummings SR et al Efficacy of continuedalendronate for fractures in women with and without prevalent verte-bral fracture the FLEX trial J Bone Miner Res 201025976-982

80 Curtis JR Westfall AO Cheng H Delzell E Saag KG Risk of hipfracture after bisphosphonate discontinuation implications for a drugholiday Osteoporos Int 2008191613-1620

81 Gallagher AM Rietbrock S Olson M van Staa TP Fracture outcomesrelated to persistence and compliance with oral bisphosphonates

J Bone Miner Res 2008231569-1575

82 Whitaker M Guo J Kehoe T Benson G Bisphosphonates for osteo-porosismdashwhere do we go from here N Engl J Med 2012366(22)2048-2051

83 Bonnick SL Shulman L Monitoring osteoporosis therapy bone min-eral density bone turnover markers or both Am J Med 2006119S25-S31

84 Kanis JA McCloskey EV Johansson H Oden A Strom O BorgstromF Development and use of FRAX in osteoporosis Osteoporos Int201021(Suppl 2)S407-S413

85 Leslie WD Berger C Langsetmo L et al Construction and validationof a simplified fracture risk assessment tool for Canadian women andmen results from the CaMos and Manitoba cohorts Osteoporos Int201122(6)1873-1883

Conflict of Interest MR McClung Sponsored presentations Am-gen Lilly Merck Novartis and Warner-Chilcott Consultation andorAdvisory Board Amgen Lilly Merck Novartis and Warner-ChilcottGrantresearch support Amgen and Merck ST Harris Sponsored pre-sentations Amgen Eli Lilly amp Company Genentech Gilead SciencesNovartis Roche and Warner Chilcott Consultation andor AdvisoryBoard Amgen Eli Lilly amp Company Gilead Sciences Merck and RochePD Miller Sponsored presentations Procter amp Gamble PharmaceuticalsAmgen Novartis Pharmaceuticals Roche Pharmaceuticals Consultationandor Advisory Board Procter amp Gamble Pharmaceuticals Merck amp CoEli Lilly Amgen Novartis Pharmaceuticals Roche PharmaceuticalsGlaxoSmithKline Baxter and Wright Scientific grants Procter amp GamblePharmaceuticals SanofiAventis Pharmaceuticals Roche Pharmaceuti-cals Eli Lilly Merck amp Co Novartis Pharmaceuticals Amgen TakedaRadius and GE D Bauer Scientific grants Novartis and Amgen KSDavison Sponsored presentations Amgen Merck Novartis Warner-Chilcott Consultation andor Advisory Board Amgen Merck NovartisWarner-Chilcott L Dian Sponsored presentations Merck Pfizer Lillyand Co Amgen Warner Chilcott Consultation andor Advisory BoardMerck Pfizer Lilly and Co Amgen Warner Chilcott DA HanleySponsored presentations Amgen Merck Eli Lilly Novartis Warner-Chilcott Consultation andor Advisory Board Amgen Merck Eli LillyNovartis Warner-Chilcott Grantresearch support Amgen Merck PfizerNPS Pharmaceuticals Eli Lilly Novartis AventisProcter and Gamble(now Warner-Chilcott) DL Kendler Sponsored presentations NovartisMerck Eli Lilly Amgen Warner Chilcott Consultation andor AdvisoryBoard Pfizer Novartis Merck Eli Lilly Amgen Research grants JampJGSK Pfizer Novartis Merck Eli Lilly Amgen CK Yuen Sponsoredpresentations Pfizer Merck and Amgen Consultation andor AdvisoryBoard Pfizer Merck and Amgen EM Lewiecki Sponsored presenta-tions Amgen Eli Lilly Novartis Consultation andor Advisory BoardAmgen Eli Lilly Novartis Merck amp Co GSK Grantresearch supportAmgen Eli Lilly Novartis Merck Warner Chilcott GSK

Authorship All authors had access to the data and a role in writing the

manuscript

msso

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ARR

ZZIAR


phosphonate therapy some bound bisphosphonate is re-leased from bone a portion binds again to bone and ismetabolically active Skeletal binding affinity increases inrank order through risedronate ibandronate alendronateand zoledronic acid1 Bisphosphonates with higher affinityare more quickly rebound in-creasing skeletal retention

The long residence time for bis-phosphonates has potential bene-fits and risks On the positive sidediscontinuation of bisphosphonatetherapy is associated with an anti-resorptive effect and antifractureprotection that persists for an un-defined period However if ad-verse effects are associated withskeletal persistence of these drugsit might take a long time for theseto resolve

ANTIFRACTURE ANDCLINICAL EFFICACY OFBISPHOSPHONATESTable 1 provides an overview ofthe antifracture efficacy with bis-phosphonates in pivotal registra-tion trials Alendronate rise-dronate and zoledronic acid decreased fracture risk at thespine nonvertebral sites and the hip alone2 whereas iban-dronate reduced vertebral but not nonvertebral fractures15

In general the efficacy of bisphosphonates changes with thepatientrsquos primary risk profilemdashthose with the highest frac-ture risk tend to have the greatest absolute reduction in

CLINICAL SIGNIF

Protection frompersists with lonphonate theraposteoporosis

The risk of osteoatypical subtroctures with amivery small compture benefits promoderate or hig

Based on currentidayrdquo from aminot justified in phigh risk for spin

Table 1 Antifracture Benefits of Bisphosphonates for the Trea

Medication (Clinical Trial) Y

Absolute Fracture RiskReduction

Vert fx Non-vert fx H

Alendronate (FIT I)4 3 71 28 1lendronate (FIT II)5 3 17 15 0isedronate (VERT NA)6dagger 3 50 32 0isedronate (VERT MN)7dagger 3 109 51 0

Risedronate (HIP)8 3 NA 18 1oledronic acid (HORIZON PFT)9 3 76 27 1oledronic acid (HORIZON RFT)10 3 NA 31 1bandronate (BONE)15dagger 3 49 09 Nlendronate (Men)17 2 50 NA Nisedronate (GIO)18 1 110 NA N

FIT Fracture Intervention Trial GIO glucocorticoid induced ostassessed nonvert fx nonvertebral fracture VERT Vertebral Efficacy wfollow-up

Widely ranging bone mineral density age and previous fracture statutable provides a broad overview of the general benefits of the therapies inpopulations studied for each therapy please refer to the referenced pub

daggerVertebral fracture incidence rate estimated from proportional hazards mode

fracture risk Hip fracture incidence decreased between1996 and 2007 in the US when bisphosphonate use waswidespread supporting a possible benefit of bisphosphonatetherapy in reducing the risk of hip fracture16

Bisphosphonates also are approved for the treatment ofmen with osteoporosis and bothmen and women receiving gluco-corticoids based on studies dem-onstrating increases in bone min-eral density Only 2 sets of thesestudies one in men and another inpatients receiving glucocorticoidshave demonstrated reductions invertebral fracture risk with 1 yearof therapy1718

The benefits of bisphosphonatetherapy extend beyond fracture riskreduction and include a decrease inmorbidity reduced health carecosts and a significant increase insurvival19-23 Oral and intravenousbisphosphonate use for up to 3 yearswas associated with a decrease inmortality of up to 28 in patientswith recent low-trauma hip frac-tures1024 Older men and womentreated with bisphosphonates over 5years had an adjusted 27 reduc-

tion in risk of death compared with nonusers21 In a recenteta-analysis the use of osteoporosis therapies including bi-

phosphonates for more than 1 year was associated with aignificant decrease in mortality in older patients at a high riskf fracture25

CE

ortant fracturesm amino-bisphos-

patients with

sis of the jaw andric femoral frac-sphosphonates iswith the antifrac-

in individuals atture risk

ence a ldquodrug hol-sphosphonates ists who remain atcture

of Postmenopausal Osteoporosis

Relative Fracture RiskReduction

Number Needed to Treat toPrevent One Fracture

Vert fx Non-vert fx Hip fx Vert fx Non-vert fx Hip fx

471 189 508 14 36 90443 111 207 60 68 447307 381 197 20 31 276376 319 182 9 20 203

NA 161 282 NA 56 91700 252 440 13 37 91

NA 290 429 NA 32 6762 11 NA 20 NA NA62 NA NA 9 NA NA70 NA NA 9 NA NA

sis HIP Hip Intervention Program hip fx hip fracture NA notdronate Therapy study vert fx vertebral fracture Y average years of

study populations make direct comparisons of therapies impossible Thisective clinical trial population For more information about the particular

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bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday

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