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Page 1: How long should we treat?

REVIEW

How long should we treat?

C. Roux & K. Briot

Received: 11 January 2013 /Accepted: 14 June 2013 /Published online: 26 March 2014# International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Abstract Osteoporosis is a chronic disease, for which ef-fective drugs are available. These drugs have reduced therisk of osteoporosis-related fractures in robust trials of 3–5 years duration. There is no evidence of anti-fracture effi-cacy for treatments of longer duration. The consequences ofstopping treatments are very different for the different mol-ecules. Bisphosphonates can be safely discontinued after 3–5 years of treatment if there was optimal adherence and ifpatients are no longer osteoporotic. This discontinuationcannot be applied in patients with recent fractures or forother treatments. Safety of prolonged treatment is a hugeconcern which must be managed appropriately. The decisionof a prolonged treatment is driven by the underlying risk offracture. This risk must be assessed regularly in order toshare with the patient the benefit-risk ratio of prolongedtreatment.

Keywords Atypical fractures . Benefit-risk ratio .

Bisphosphonates . Fractures . Long-term treatments .

Osteoporosis . Osteonecrosis of the jaw . Stopping treatment

“La question ne se pose pas : il y a trop de vent (Boris VIAN)”

Introduction

Osteoporosis is a medical condition characterized by an in-creased risk of fractures. Hip fractures are the most devastatingfractures, but attention must be paid also to vertebral fractures[1, 2] and to some, nonvertebral nonhip fractures which carryan excess mortality in the years following the fracture [3–7].

Moreover, these fractures are strong risk factors for otherfractures [8, 9] and the 5-year mortality in patients with subse-quent fractures is higher than in those with only one event [1].Patients with a high risk of fracture can be identified by bonemineral density (BMD) measurements and fracture risk assess-ment tools, such as FRAX®, which integrates clinical riskfactors, with or without BMD, to predict an individual 10-year risk of sustaining a fracture. For patients who have a highrisk of first or recurrent fracture, both nonpharmacological andpharmacological approaches must be implemented. Severalpharmaceutical treatments exist for the management of osteo-porosis that effectively reduce the risk of vertebral,nonvertebral, and hip fractures. Proof of their efficacy is robust,as demonstrated in postmenopausal women in clinical trials ofoptimal methodology, (prospective placebo-controlled design),assessing fractures as the principal outcome. However, durationof these studies is 3–5 years; a chronic condition such asosteoporosis requires long-term treatment. The proportion offrail elderly persons at high risk of falls and fractures isexpected to increase dramatically in the next decades. Indeed,human senescence has been delayed: the age at whichremaining life expectancy is 10 years has been postponed by8 years in Sweden, 12 years in Japan; in some countries, thenumber of centenarians climbs vertically [10]. This has pro-found implications not only for societies but also individuals,who expect to reach old age in good health. Moreover, severeosteoporosis and fractures are not only a problem for elderlypeople but can occur in 60-year-old patients [11], and datasuggest that the consequences of fractures can be more severein the younger rather than in the older patients. In the Study ofOsteoporotic Fractures, a total of 5,580 women were observedprospectively for two decades: increased short-term mortalityafter hip fracture was in fact driven by the excess mortality inthose aged 65–69 years [odds ratio (OR)=5.0 (2.6–9.5)] and70–79 years [OR=2.4 (1.8–3.3)] [12]. Thus, treatment can beimplemented in 60-year-old patients. How long these patientsshould be treated is a key issue.

C. Roux (*) :K. BriotDepartment of Rheumatology, Cochin Hospital, Paris-DescartesUniversity, Paris, Francee-mail: [email protected]

Osteoporos Int (2014) 25:1659–1666DOI 10.1007/s00198-013-2433-3

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In this review, we summarize available data, with a specialfocus on safety, and discuss indications for prolonged anti-osteoporotic treatment. For hypothetical purposes, we willconsider that patients have optimal adherence to the pre-scribed drug, to calcium and vitamin D supplements if theyare necessary, and to nonpharmacological treatments. Fallprevention programs are beneficial in elderly people with highrisk of falling, by reducing the number of falls and the numberof fallers [13]. Assessment and correction of postural instabil-ity, excess of antihypertensive drugs or hypnotics, poor visualacuity, etc. [14] can help decrease the risk of falls and frac-tures. In a clinical setting, it is intuitive that this approachparticipates in the optimization of patients'care.

Is anti-fracture efficacy sustained with long-termtreatment?

Some data in the placebo-controlled trials suggest that theanti-fracture effect of some drugs is stronger in the first yearof treatment: the relative risk of vertebral fracture is de-creased by 45 % over 1 year, 39 % over 3 years and 24 %over 5 years with strontium ranelate [15]; this risk is de-creased by 65 % over 1 year but 41 % over 3 years withrisedronate [16]. This apparent reduction of effect can beexplained by a higher proportion of placebo-treated subjectswho experience incident fractures and are censored. Thus,the level of risk of fracture within the placebo group coulddecrease with time. Such a result has not been observed withtwo injectable drugs, zoledronic acid [17] and denosumab[18]; in these studies, the incidence of fractures in the place-bo groups was lower than in trials cited above; moreover,completion may be higher in studies with parenteral drugs.

To provide long-term data, extension studies have beenconducted with most of the treatments. The reliability of theseextension studies is low, because of the absence of placebo,(precluding any definitive conclusion about anti-fracture effi-cacy), and selection of patients, i.e., those with optimal adher-ence, good tolerance, and low risk of fracture. However, havingthese limitations in mind, these studies give information for themanagement of patients who require long-term treatment.

The Multiple Outcomes of Raloxifen (MORE) trial wasconducted over 3 years, and had a 12-month blinded exten-sion [19], confirming the anti-vertebral fracture effect. Con-tinuing Outcomes Relevant to Evista study was a random-ized placebo-controlled extension of MORE, providing 8-year data for raloxifene. From the 7,705 patients included inMORE at baseline, 4,011 chose to enroll, and the mediantime between the two studies was 10.6 months. Raloxifenehad no effect on nonvertebral fracture risk after 8 years.However, the main objective of the trial was to assess theincidence of breast cancer, and no spine radiographs wereperformed [20].

The anti-fracture effect of strontium ranelate has beendemonstrated over 5 years against placebo; the long-termeffect of strontium ranelate has been explored up to 10 yearsin an open-label extension study [21]. From the 3,082 pa-tients who received strontium ranelate in the pivotal studies,893 were included in the first extension study after 5 years ofplacebo-controlled period, and 237 patients, who receivedstrontium ranelate for 10 years, are the basis of this observa-tion. These patients had baseline characteristics similar to thewhole population. The cumulative incidence of new frac-tures was similar during the 5-year extension period andduring the first 5-year placebo-controlled period, 20 % onaverage. An effort was made to approach the anti-fractureefficacy of strontium ranelate in the absence of a placebogroup by comparing the results to the ones predicted byusing the FRAX value (without BMD; mean, 26 %) inpatients at the time of their inclusion in the extension study.

Fracture Intervention Trial Long-Term Extension (FLEX)is an extension of the pivotal Fracture Intervention Trial(FIT) study of alendronate with 10-year follow-up. Fromthe initial 3,236 patients assigned to receive alendronate inthe FIT trial, 1,099 were randomized in FLEX: 437 in theplacebo group and 329 and 333 in the alendronate group, 5and 10 mg per day, respectively [22]. Because women couldreceive a placebo after randomization, those with a low hipBMD (T<−3.5) or with BMD loss during FIT were notincluded; thus at baseline of FLEX, only 30 % of patientshad a femoral neck T-score≤−2.5 and more than 40 % ofpatients had a femoral neck T-score>−2.0. No significantdifference between placebo and alendronate (two dosespooled) was observed for all clinical fractures ornonvertebral fractures. There was a statistically significantlower risk of clinical vertebral fractures, without differencein the risk of morphometric vertebral fractures [22].

The longest follow-up of patients in risedronate trials is7 years, in a group of 68 patients [23]. It was observed asimilar annualized incidence of new vertebral fractures dur-ing years 6–7 and years 0–3 (which was the initial placebo-controlled study).

In a cohort from a large USA medical claims database,287,099 patients with oral bisphosphonate prescription wereidentified: with the methodological limits of such studies,data suggest persistence of overall hip fracture protectionwith long-term, up to 8 years, use of bisphosphonates [24].

From the initial 2,629 patients who received three infusionsin the Reduced Incidence with Zoledronic Acid (HORIZON)pivotal fracture trial, 1,233 were randomized to a 3-yearextension study: 470 completed follow-up in the placebogroup and 451 in the yearly zoledronic acid group (407received three doses). At baseline of the extension period,the mean age of participants was 75.5 years, 53–57 % of themhad a femoral neck T-score≤−2.5, and 30–36 % had at leasttwo prevalent vertebral fractures. No significant differences

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between treatment groups were observed for all fractures,except morphometric vertebral fractures; there was no differ-ence for clinical vertebral fractures [25].

Of the 7,808 participants to the pivotal 3-year study ofdenosumab (FREEDOM trial), 4,550 were enrolled in anextension study with an open-label design for an additional7 years. Data have been reported for the two first years ofextension, making available fracture data in patients exposedto 5 years of denosumab (2,343 patients); in the extension,fracture incidence rates remained low, similar to the yearlyincidence observed during FREEDOM. The expected frac-ture rates in a hypothetical cohort of long-term placebocontrols was estimated by the method of “virtual twins”,and these calculated incidences were higher than the ob-served incidences in the treated patients [26].

From a methodological point of view, there is no evidencethat anti-fracture efficacy exists after 3–5 years. From a prac-tical point of view, there is no evidence that bisphosphonatesstop working beyond 3–5 years of treatment, for a period oftime. Provided data are reassuring, although there is a biasrelated to selection of patients. Whether or not a switch toanother treatment could help for anti-fracture efficacy isunknown.

Is there a risk related to stopping treatment?

Cessation of some treatments results in decrease in BMD. Thisis well known for hormone replacement therapy (HRT). After2 years of treatment with conjugated estrogen 0.625 mg/day, 81women were switched to placebo, and during the next year theyexperienced a 4.5 and 2.4%decrease at the spine and trochanter,respectively [27]. More importantly, the post interventionfollow-up of the Women’s Health Initiative trial including15,730 women, which demonstrated that HRT reduces hipand clinical vertebral fractures, showed that the risk offractures was comparable among women in the discontinuedHRT group and placebo group; this suggests a greaterincrease in the annualized risk of fractures in women afterHRT therapy [28]. One year of discontinuation of raloxifene(after 5 years of administration) results in 2.4 % decrease inlumbar spine BMD [29].

Such accelerated bone loss has also been observed afterwithdrawal of denosumab. In an off-treatment extension of arandomized, double-blind study, 128 patients were followedfor 2 years after a 2-year treatment period. BMD decreased atall sites; most of the decrease occurred during the first yearafter cessation of treatment. After 2 years off treatment,BMD was not different to pretreatment value at the spineand hip but lower at the radius [30]. After denosumab dis-continuation, the bone resorption marker increases immedi-ately, above the baseline values, peaks 6 months after dis-continuation, and returns to pretreatment values. There is a

statistically significant correlation between resorption mark-er value before treatment and after 2 years of treatmentcessation. The key issue of potential effect of these variationson fracture risk has been assessed in 797 subjects in FREE-DOM who discontinued treatment after receiving 2 to 5doses of either denosumab or placebo. They were followedfor a median of 0.8 years per subject; 42 and 28 % of theprevious placebo and denosumab groups, respectively, re-ceived an anti-osteoporotic treatment during the follow-up.There was no difference in fracture occurrence pattern be-tween the groups during the off-treatment period. These datahave been obtained in a population with a mean baseline T-score of −2.8 and −2.1 at the lumbar spine and hip, respec-tively, and only 26 % of patients had prevalent vertebralfractures [31]. Thus, these reassuring data do not apply to ahigher-risk population.

Long-term bone retention is a well-known pharmacolog-ical property of bisphosphonates, although not similar for allthe molecules. Patients are still exposed to these drugs afterthey stop taking them.

The fracture risk after discontinuation of risedronate hasbeen assessed after 3 years of treatment. Initially, 1,628patients were randomized to receive either placebo orrisedronate 5 mg and 759 entered a 1-year follow-up study[32]. The relative risk of vertebral fractures was reduced by46 % in the former risedronate group compared to the formerplacebo group. In contrast, there was a −0.8 and −1.23 %decrease in lumbar spine and femoral neck BMD, in theprevious risedronate treated patients. Urinary NTX as amarker of bone resorption was available at the end of thefollow-up in 89 patients of the former risedronate group: itincreased from 30 to 51 nmol BCE/nmol creatinine. Thesedata suggest a discrepancy between the short-term changesof surrogate markers and vertebral fracture risk. This limitstheir use in clinical practice for predicting vertebral fracturerisk in the year after cessation of risedronate treatment.Whether or not bone turnover marker changes can help todecide when to resume treatment is unknown.

In FLEX [22], patients switched to placebo had a 1.5 %increase in lumbar spine BMD and a 3.38 % decrease in hipBMD over 5 years. Biochemical markers were assessed in asubgroup of 87 patients, and the first assessment wasperformed 3 years after cessation of alendronate. A gradualrise in markers was measured over 5 years, with a value 50 to60 % higher than in patients who continued alendronate.This study does not give information on changes in markersin the first years after cessation of alendronate [22].

In the extension study of HORIZON [25], patientsswitching to placebo after 3 years of zoledronic acid treat-ment had after 3 years of follow-up, a slightly lower BMDthan patients who continued treatment (with differences of1.36 and 2.06 % at the femoral neck and lumbar spine,respectively). There was no difference in markers of bone

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turnover at year 6 between patients continuously treated over6 years or switched to placebo after 3 years of treatment.

Post hoc analyses have been conducted in order to assessthe determinants of long-term anti-fracture effects. Data arelimited by methodological issues precluding any definitiveconclusion on fracture effect. These data suggest that BMDmeasurements of the femoral neck could be used to selectpatients for prolonged therapy. In FLEX, among womenwithout vertebral fracture at baseline, continuation ofalendronate reduced nonvertebral fractures in those havinga femoral neck T-score of −2.5 or less. Such a benefit was notobserved in those having a higher T-score. These resultscannot be applied to patients with vertebral fractures atbaseline, though it is the most likely population to treat[33]. The predictive value of a T-score<−2.5 at the femoralneck was confirmed at the end of a 3-year period ofzoledronate treatment [34].

There are strong differences between drugs in bone pa-rameter changes after cessation of treatment; the answer tothe question about the consequences of stopping treatmentmust be drug-specific. With bisphosphonates, data suggestthat patients without hip osteoporosis at the end of 3–5 yearsof treatment may not have deleterious effects from a “drugholiday.” Benefits, even if persisting for some time, are notpermanent, and this “drug holiday” is usually only a tempo-rary suspension of treatment. No data support such a strategyin patients with recent fractures, nor in patients receivingother treatments.

Is it harmful to prolong treatment?

A number of side effects of anti-osteoporotic treatments havebeen described in clinical studies. Physicians are aware ofthe risk of gastro intestinal side effects with oralbisphosphonates, potential nephrotoxicity of intravenousbisphosphonates, venous thrombo-embolism risk with ralox-ifene, strontium ranelate, etc.. These risks have been identi-fied in pivotal studies without evidence for increase withtime. But post marketing reported cases, small series, andstudies about long-term adverse events of bisphosphonateshave been published during these last years and receivedconsiderable public exposure. Although this risk is verylow, the perception of this risk is very high. This contrastsdramatically with the failure to perceive increased risk ofosteoporosis-related fractures [35]. This discrepancy leads todifficulties in daily practice, as it affects adherence to treat-ment and necessitates careful information of the patients.

Two studies published in 2010, using the same UK Gen-eral Practice Research Database had contradictory conclu-sions regarding the risk of esophageal cancers with oralbisphosphonates. The first one used a nested case–controlmethodology (one case of cancer, and five controls matched

for age, sex, general practice, and observation time), toassess the risk related to oral etidronate, alendronate, andrisedronate [36]. The incidence of esophageal cancer wasincreased in people with one or more prescription (RR=1.30(1.02–1.66)) and was higher with use over 5 years; for thisduration of prescription, it was estimated that the incidenceof esophageal cancer at age 60–79 years increased from anexpected 1/1,000 to 2/1,000. The second study used a cohortmethodology in the same database, bisphosphonates usersand controls being matched by age at the time of the firstprescription [37]. There was no increase in risk of esopha-geal or gastric cancer (HR, 0.96 (074–1.25) and 1.07 (0.77–1.49), respectively) and no effect of duration of bisphospho-nate intake. In a register-based open cohort study usingnational healthcare data in Denmark [38], alendronate usershad no increased risk of esophageal cancer (OR=0.71 (0.43–1.19)) and a lower risk of gastric cancer (OR=0.61 (0.39–0.97)). Risk reduction was greater in long-term users. Thisstudy raises an important point, i.e., that alendronate userswere more likely to have gastroscopy. In a meta analysis ofseven studies (19,700 esophageal cancers), a relationshipbetween bisphosphonates and esophageal cancer (OR=1.74(1.19–2.55)) was observed, with an increase for a long peri-od of administration [39]. Heterogeneity was high, and theincreased risk was associated with etidronate use, not withalendronate use [39]. In another meta analysis of sevenstudies (3,775 esophageal cancers), there was no associationbetween cancers and bisphosphonates [40]. A relevant ob-servation is the reduced colon cancer incidence (HR, 0.69(0.60–0.79)) and decreased mortality once colon cancer isdiagnosed (HR, 0.82 (0.70–0.97)) in bisphosphonate users[41]. The same database in Denmark also suggested a de-crease in the risk of dying of esophageal cancers [41].

Osteonecrosis of the jaw (ONJ) is a serious complicationin patients with malignant bone diseases treated with intra-venous bisphosphonates. In contrast, it is a very rare event inosteoporotic patients. There are a number of limitations instudies, including small sample size, retrospective design,inadequate duration, or voluntary reporting of cases. This isillustrated by the huge discrepancy in reported estimatesfrom 0.00038 % (three cases out of 780,000 patients in theGerman Central register of the Charité Hospital in Berlin)[42] to 4 % (nine cases out of 208 patients in a retrospectivereview of electronic medical record system at the Universityof Southern California School of Dentistry) [43]. Accordingto the American Society for Bone andMineral Research TaskForce, the rate of this event is estimated between 1/10,000 to1/100,000 [44]. For the American Dental Association Coun-cil on Scientific Affairs, the prevalence is lower than 1/1,000,and no studies adequately address incidence [45]. So far,there is no strong evidence that the risk of ONJ increaseswith the duration of bisphosphonate treatment. One studysuggesting such an effect of treatment duration dealt with

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nine cases (diagnosed in a survey of 13,946 subjects, with8,572 survey respondents): no cases were reported amongthe 2,191 subjects with less than 2.5 years of treatment [46].Two cases of osteonecrosis of the jaw were reported in thesixth year of exposure to denosumab among 2,343 patients[26]. Recommendations are now published for prevention ofthis event, including regular dental visits, maintaining excel-lent oral hygiene, and communication between all membersof the healthcare team. Such recommendations must beimplemented among the prescribers, and dentists, to avoidmisconceptions and inappropriate interruption of treatments.According to the American Dental Association, the decisionto stop antiresorptive therapy must be weighed against therisks associated with the underlying bone disease [45].

The first cases of atypical subtrochanteric and diaphysealfemoral fractures in patients receiving bisphosphonates werereported in 2007. No case has been reported in clinicalstudies with these drugs, even studies of prolonged duration[22]. A task force of the American Society for Bone andMineral Research clarified the definition of these fracturesand the diagnostic criteria [47]. Attention has been paid topotential errors in the use of administrative databases [48].The absolute risk of such fractures in bisphosphonates usersis very small: the incidence rate is 32 cases per millionperson-years [49] in a case–control study conducted at theUniversity Hospital of Geneva, Switzerland. In the NationalSwedish Patient Register, the difference in the risk of atyp-ical fracture between users and nonusers of bisphosphonateswas five cases per 10,000 patient-years [50]. These studiesshow that atypical fractures can occur in patients withoutbisphosphonates, which are thus a risk factor and not anecessary cause. One case of midshaft femur fracture hasbeen adjudicated as atypical femoral fracture in the long-term extension study of denosumab [51]. The key issue isthat these atypical fractures could be related to the durationof the treatment. From a large US health maintenance orga-nization, it was estimated that the atypical femoral fractureincidence increased from 2 per 100,000 cases per year for2 years of bisphosphonate use to 78 per 100,000 cases peryear for 8 years of use [47]. According to a study, conductedon 39 cases of atypical fractures (and 438 regular fractures),a longer duration of treatment is associated with higher risk[49]. In the Healthy Bones Program at Kaiser SouthernCalifornia, 188,814 patients had used bisphophonates over5 years; 142 subjects had atypical fractures: 128 had bis-phosphonate exposure. The age adjusted incidence rates foran atypical fracture were 1.78/100,000/year with exposureless than 2 years and 113.1/100,000/year with exposure from8 to 10 years [52]. It is not clear why some patients withbisphosphonates develop such atypical fractures, and addi-tional data are needed to further define a subgroup of patientsfor whom risks of antiresorptive treatments are high. Arecent study made the observation that the majority of 81

patients with atypical fractures had osteopenia rather thanosteoporosis at the time they began bisphosphonate treat-ment [53]; the role of baseline BMD in this risk needs to beclarified. The risk of atypical femoral fractures decreasesfollowing discontinuation of oral bisphosphonates, with a70 % reduction in risk for every year since the last use [50].

Side effects of anti-osteoporotic treatments exist, are veryrare, and paradoxically very well known by the public. Wemust not neglect them. However, the number of subjectsneeded to harm is dramatically higher than the numberneeded to treat in the population of osteoporotic patients athigh risk of fracture.

Discussion and conclusion

Two pitfalls must be avoided while discussing the durationof anti-osteoporotic treatment: (1) “there is no evidence ofanti-fracture efficacy beyond 5 years, thus, the treatmentsmust be stopped.” The advocates of this attitude do notexplain how to manage individuals with persistent high riskof fracture. (2) “Osteoporosis is a chronic disease, as ishyperlipemia, and treatments of chronic diseases are neverstopped; thus, anti-osteoporotic treatments are lifelong treat-ments.” But in contrast to other treatments of chronic dis-eases, anti-osteoporotic treatments induce relevant changesin mass and/or structure of the target organ, i.e., the skeleton,and the effects of these changes during a lifelong treatmentcannot be studied. Thus, we need to go on without strongevidence-based data, from a general routine attitude to apersonalized one. Which objective parameters can be usedto take the appropriate decision? Some are related to thepatient, some to the treatment.

It is logical to consider that an elderly frail woman, with ahigh risk of falls because of orthopedic or neurologicaldisturbances and a previous osteoporotic fracture, can re-ceive a lifelong anti-osteoporotic treatment? Indeed,refractures contribute substantially to overall mortality asso-ciated with fracture [54]. In other individuals, fractures,BMD, and age, which are the parameters used when decidingto begin a treatment, can also be used to decide on duration.Fractures cluster in time after the first fracture [55],supporting the efficacy of early treatment in an optimaltherapeutic window in the years following the first fracture.But the association between prevalent fractures and the sub-sequent ones wanes with increased time [56]. This raises thehypothesis that the duration of a treatment could be differentin a patient with a recent fracture and another who sustaineda fracture several years before the beginning of the treatment.BMD is a strong determinant of fractures and, although theywere obtained in post hoc analyses, current data suggest thatpersistent osteoporosis, at the femoral neck, is an indicationto prolonged treatment. However, these data were obtained

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in patients aged 70–75 years [33] and whether a residual lowBMD could be acceptable in younger patients is unknown.

If BMD at treatment end is a determinant of the decision toprolong treatment, could BMD be the target to treat? Such astrategy raises clinical and therapeutic concerns. First, we treatpatients with fragility fractures, whether or not their T-score isbelow<−2.5. This target to treat is thus useful only in aproportion of fragile patients. The consequence is that treat-ment duration could be shorter in fractured patients withoutlow BMD, as compared to those with a T-score<−2.5, pro-vided the overall estimation indicates a low risk of refracture.For alendronate, risedronate, and raloxifene, the relationshipbetween drug-induced BMD changes and anti-fracture effica-cy is not established, but stronger correlations have beenobserved with zoledronate [57] and denosumab [58]. Whetherthis strong correlation reflects a better adherence or a higherpotency of the drugs can be debated. The key issue for clinicalmanagement of the patient is the relevance of BMD at the endof the first sequence of treatment, which can be measured atthat time for an appropriate decision.

Larger increases in BMD have been observed with sometreatments, of different mechanisms of action (denosumab[26], odanacatib [59]), thanwith bisphosphonates. That meansthat the probability of achieving the BMD goal may be higherwith these molecules; this could justify providing detailedinformation on safety, prolonged treatment. For some patientswith a very low BMD, for whom the target may not be easilyattainable, a strategy of therapy combination, or the use of ananabolic agent (teriparatide, anti-sclerostin) followed by an-other treatment to maintain the benefit, can be considered.Thus, discontinuation of treatment cannot be a general recom-mendation, as there are strong differences among treatments inbone response to cessation of treatment. Available data sug-gest that therapeutic gain is not compromised in some patientsdiscontinuing bisphosphonates, but this is not true for HRT,and unknown for other treatments. It is worrisome to observethe substantial changes in bone remodeling markers and BMDafter cessation of some treatments in fragile osteoporoticpatients. Switching therapies to maximize the benefits andminimize the risks is a possibility, but data are lacking aboutthis strategy, in particular for switches between antiresorptivedrugs.

The decision of prolonged treatment must be based on acomprehensive assessment of the risk of fracture. The obser-vation that treatment with bisphosphonate can be stoppedafter 3–5 years, provided that the patients are no longerosteoporotic, is a good indication for further studies. In in-dividuals with persistent high risk, there is no reason to stopthe treatment [60–62] and information must be givenabout potential side effects. This information is justifiedbut should not discourage osteoporotic patients from re-ceiving long-term treatment provided that their risk offracture is still high.

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Conflicts of Interest Christian Roux: research grants and/or honorar-ia from AMGEN, LILLY, MSD, NOVARTIS, PFIZER, ROCHE,SERVIER, and UCB. Karine Briot: research grants and/or honorariafrom AMGEN, LILLY, MSD, NOVARTIS, PFIZER, ROCHE, andSERVIER.

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