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Therapeutic holidays in osteoporosis: Long-term strategy of treatment with bisphosphonates
Vacaciones terapéuticas en osteoporosis: estrategia en el tratamiento a largo plazo con bifosfonatos
a Servicio de Medicina Interna, Hospital Universitario Infanta Leonor, Madrid, Spain
b Servicio de Ginecología y Obstetricia, Hospital Universitario Cruces, Baracaldo, Vizcaya, Spain
c Servicio de Reumatología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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FN: femoral neck; BMD: bone mineral density; Fx: fracture; BRM: bone remodelling markers.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Osteoporosis is a chronic disease, like other diseases such as hypertension or diabetes mellitus, requires indefinite treatment. This does not mean that drug administration must necessarily be permanent or that the administered drug should always be the same, and, of course, treatment discontinuation will always be justified when the risk/benefit ratio becomes unfavourable.</p><p id="par0010" class="elsevierStylePara elsevierViewall">This scenario arises in the following situations: when the therapeutic goals are reached, when there is loss of efficacy or when the risk of developing side effects increases.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The objectives to be achieved in the treatment of osteoporosis are not well defined and they need to be individualized depending primarily on the patient's fracture risk at any time during the evaluation. In general, we can distinguish three different scenarios:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">(1)</span><p id="par0020" class="elsevierStylePara elsevierViewall">When there is no previous fracture: the therapeutic objective can be set to −2.5 T-<span class="elsevierStyleItalic">score</span> in the femoral neck, so that when this value is reached, the treatment could be withdrawn.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">(2)</span><p id="par0025" class="elsevierStylePara elsevierViewall">When there is a previous fracture which occurred before the last 3–5 years (in fact, probably, before starting the treatment): the densitometric goal should be a little more demanding: −2.0 T-<span class="elsevierStyleItalic">score</span>. Reached this value, treatment may be temporarily suspended.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">(3)</span><p id="par0030" class="elsevierStylePara elsevierViewall">If a previous fracture has occurred in the last 3–5 years (when the patient was probably already in treatment), the patient should continue treatment regardless of the bone mineral density (BMD) value.</p></li></ul></p><p id="par0035" class="elsevierStylePara elsevierViewall">The objectives achieved tend to disappear quickly after treatment discontinuation (resumption of bone loss), so a definitive treatment withdrawal is hardly warranted. So, with osteoforming (teriparatide), antiresorptive (raloxifene, bazedoxifene, denosumab) treatments and dual mechanism drugs (strontium ranelate), discontinuation of treatment results in a gradual loss of the beneficial effect achieved and in the progressive loss of BMD. Bisphosphonates (BPs) are the only exception to this fact.</p><p id="par0040" class="elsevierStylePara elsevierViewall">BP's bone affinity provides a osteoprotective “lingering effect” on BMD and even on the onset of the antifracture effect after being discontinued, as demonstrated in the study <span class="elsevierStyleItalic">Fracture intervention trial Long-term EXtension</span> (FLEX).<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Is safety being as important as its efficacy. Besides being effective in the treatment of osteoporosis, BP drugs have an excellent safety profile.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">2–5</span></a> The fracture risk reduction with BP ranges between 40 and 70% for vertebral fracture and 40–50% for femur fracture. Besides, BPs have also shown a reduction in mortality. However, prolonged use may be associated with adverse effects that were not described in the main drug approval trials. According to the latest data, the risk of osteonecrosis of the jaw with oral BP is: OR 2.32 (95% CI 1.38–3.91).<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">6,7</span></a> Moreover, the absolute risk of atypical fractures of the femur (AFF) in patients treated with BP range from 3.2 to 50 cases per 100,000 people treated per year, and increases with prolonged exposure.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8–10</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Concept of therapeutic holidays</span><p id="par0050" class="elsevierStylePara elsevierViewall">Strictly speaking, “therapeutic holidays” refer to the temporary interruption of osteoporosis treatment with BP (alendronate [ALN], risedronate [RSN], ibandronate [IBN] or zoledronate [ZLN]) with the intention of making its probable antiresorptive “persistent effect” last longer given the fixing effect these drugs have on bone tissue, while minimizing the possible occurrence of any of the complications associated with its use, which have shown to be more frequent the longer the treatment is. The term “holiday” implies that, at some later stage, the same drug will be reintroduced again.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The main purpose for which therapeutic holidays with BP arise is to maintain a proper balance between benefit (efficacy or effectiveness to prevent the occurrence of osteoporotic fractures) and the safety associated with the long term use of a particular BP for more than 3–5 years.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Of all the complications described with BP, the gradual emergence of AFF cases is what has alerted and questioned the long-term treatment with these drugs. From a pathophysiological point of view, it seems that long term treatment with BP leads to excessive suppression of bone remodelling, a situation resulting in greater mineralization, accumulation of aged bone without remodelling and, therefore, a higher risk of microfractures.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> However, this has not been fully demonstrated in histological studies with patient series.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">12,13</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Another reason to take into account in connection with implementing “therapeutic holidays” is undoubtedly the low adherence of patients to an indefinite treatment, although whether these scheduled interruptions increase compliance still needs to be demonstrated and, additionally, we cannot ignore the pharmaceutical cost.</p><p id="par0070" class="elsevierStylePara elsevierViewall">However, this strategy is only acceptable for treatment with BP, and not for other drugs used in osteoporosis, such as denosumab, oestrogen receptor modulators, teriparatide, or strontium ranelate.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pharmacokinetics of bisphosphonates</span><p id="par0075" class="elsevierStylePara elsevierViewall">BPs, especially the aminated ones, such as ALN, RSN, IBN or ZLN, are potent antiresorptive agents which slow down resorption markers in an intense and sustained manner, even after several years,<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">14–16</span></a> while significantly increase BMD.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Pre-clinical and experimental studies have shown that, after absorption, the BPs are deposited in the bone or rapidly eliminated in the urine, with minimal accumulation in non-calcified tissues. In the case of ALN, 50% of the drug will be retained in the skeleton, after a single dose, in the first week of treatment, while the other 50% will be excreted in the urine. Subsequently, retention is much slower and progressive, so that in the sixth month the skeletal retention amounts to 67%. Simultaneously, renal elimination is also slow and gradual, so that after several years, the drug is still being eliminated, estimating a terminal half-life of over 10 years.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">After fixation in the bone's hydroxyapatite and performing its antiresorptive effect, and as a result of the coupled bone formation, ALN is “embedded” in the bone matrix and remains there for a while, probably inactive.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a> Later, following a new activation on the remodelling units, part of the ALN embedded in the bone with high turnover is released again, becoming active and continuing with its antiresorptive effect. In fact, in ALN's Summary of Product Characteristics, it mentions that if the treatment is discontinued after 10 years (at a dose of 70<span class="elsevierStyleHsp" style=""></span>mg/wk), the estimated blood circulation skeletal release would be approximately the same as the one that would occur by oral administration at doses of 2.5<span class="elsevierStyleHsp" style=""></span>mg/day.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Differences between bisphosphonate agents</span><p id="par0090" class="elsevierStylePara elsevierViewall">Despite sharing a similar molecular structure (2 phosphate groups linked by a carbon atom), not all BPs are the same (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Although the R1 chain is constant across BPs (OH group) and is responsible for the affinity to bone hydroxyapatite, the R2 chain is variable and is responsible for the antiresorptive potency, that is, determines the ability to inhibit phosphoribosyl pyrophosphate synthetase of the osteoclast, essential enzyme to maintain the function and viability of this cell.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">1,6,7,10</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Therefore, there are differences in both, affinity for bone tissue and antiresorptive potency between different BPs. For example, among the most used amino bisphosphonates in osteoporosis, IBN and RSN are among those with a lower affinity for hydroxyapatite, followed by ALN, being ZLN the BP with higher affinity and, therefore, less bone releasability. Regarding the antiresorptive potency, ALN is the one having a lower potency, followed, in order, by IBN, RSN and ZLN. Thus, the conclusions on ALN treatment interruption studies are not entirely extrapolated to the rest of BPs.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Comparison of the efficacy of continued treatment with bisphosphonates versus therapeutic holidays</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Maintenance versus alendronate suspension</span><p id="par0100" class="elsevierStylePara elsevierViewall">The largest study published to date where the effects of maintained or discontinued treatment with ALN on BMD and fractures are evaluated is the FLEX study.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> It is the <span class="elsevierStyleItalic">Fracture Intervention Trial</span> (FIT) extension study<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> on treatment of postmenopausal osteoporosis with ALN. Of the more than 3000 patients in the FIT study who received ALN for at least 3 years (5<span class="elsevierStyleHsp" style=""></span>mg/day for the first 2 years and 10<span class="elsevierStyleHsp" style=""></span>mg/day thereafter), those who had received at least an extra year of ALN treatment after the end of FIT at a dose of 10<span class="elsevierStyleHsp" style=""></span>mg/day were chosen to participate in the FLEX study. Also, they needed to have a total hip BMD above the FIT baseline, with a T-<span class="elsevierStyleItalic">score</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>−3.5. 1099 women (437 placebo, 329 ALN 5<span class="elsevierStyleHsp" style=""></span>mg/day and 333 ALN 10<span class="elsevierStyleHsp" style=""></span>mg/day) were randomized to be treated for 5 additional years. In this way it was possible to compare the group of women who had received ALN (any dose) for 10 years and the group of women who had received ALN for 5 years and then placebo for 5 years.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The population of the FLEX study corresponded to postmenopausal women with an average age of 73 years, with low femoral neck BMD (mean T-<span class="elsevierStyleItalic">score</span> −2.2) and 34% of vertebral fractures.</p><p id="par0110" class="elsevierStylePara elsevierViewall">The group receiving ALN for 10 years managed to increase the lumbar spine BMD and remained stable regarding the hip BMD (total hip, femoral neck and trochanter) throughout the study period. By contrast, the group which discontinued the treatment with ALN at 5 years showed a progressive decrease in hip and spine BMD compared to the group treated with ALN for 10 years. Thus, lumbar spine BMD was 3.7% (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) and hip BMD was 2.4% lower in total hip (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001); 1.9% lower in the femoral neck (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) and 3.2% lower in trochanter (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). However, BMD values in the group of 5 years remained higher than the values 10 years before, prior to initiating ALN treatment.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Regarding bone remodelling markers (BRM), women who continued with ALN maintained low and stable marker levels (both resorption and bone formation), while women who discontinued treatment experienced a gradual increase in these markers, even though at the end of 5 years without treatment, markers were still somewhat below baseline before starting the FIT (10 years earlier).<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">However, the most important finding of this study was the analysis of fractures, since no significant differences in the incidence of new vertebral (morphometric) and non-vertebral fractures among women receiving ALN for 10 years were observed and those who discontinued treatment at 5 years. However, there were differences observed in clinical vertebral fractures, these were 45% lower in the group of women who maintained treatment with ALN for 10 years.</p><p id="par0125" class="elsevierStylePara elsevierViewall">However, we must take into account the limitations of this study, in which the treatment group who received ALN for 10 years corresponded to the sum of the patients with 5 and 10<span class="elsevierStyleHsp" style=""></span>mg daily. In addition, at the time of inclusion in the FLEX study there was up to 22% of patients who had already left the treatment with BP.</p><p id="par0130" class="elsevierStylePara elsevierViewall">The most important conclusion of this study is that continued treatment with ALN for 10 years keeps the antiresorptive effect, increases BMD in the lumbar spine (approximately 5% in 5 years), maintaining femoral BMD stable, reducing the risk of clinical vertebral fractures versus patients who discontinued treatment at 5 years. However, if the drug is withdrawn at 5 years, the antiresorptive effect is slowly lost in the next 5 years, with slow and progressive decrease in femoral BMD (<3%), although the anti-fracture efficacy is maintained, both morphometric and peripheral vertebral fracture.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Maintenance versus suspension of risedronate</span><p id="par0135" class="elsevierStylePara elsevierViewall">One of the few studies that compares maintained versus interruption of RSN treatment is the one published by Watts et al.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a> It is the <span class="elsevierStyleItalic">Vertebral Efficacy with Risedronate Therapy-North America</span> study population, where fracture reduction was 41% after 3 years of treatment with RSN. It was observed that, although patients who discontinued treatment with RSN experienced a loss of BMD in the femoral neck, RSN anti-fracture effect remained one year after the suspension (up to 46% reduction of fractures in the group treated for 3 years with one year of rest compared to the untreated control group during the 4 years).</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Maintenance versus suspension of zoledronate</span><p id="par0140" class="elsevierStylePara elsevierViewall">ZLN has shown something similar. Comparing continued treatment up to 6 years versus administering it for only 3, femoral bone loss was observed, but not at the lumbar spine, increasing the BRM in the untreated group, with a higher incidence of morphometric vertebral fractures in untreated patients (6.2% versus 3% in the groups treated for 3–6 years, respectively; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05).<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Maintenance versus suspension of ibandronate</span><p id="par0145" class="elsevierStylePara elsevierViewall">There are no data comparing different treatment periods with IBN, therefore, we can say that there is no scientific evidence today regarding favouring therapeutic holidays with this drug.</p><p id="par0150" class="elsevierStylePara elsevierViewall">As a final comment on the BP studies discussed, we can conclude that, although in general the anti-fracture effect is maintained throughout the years following treatment discontinuation, there is some disparity in the appearance of clinical or morphometric vertebral fractures in the different studies.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Selecting patients for therapeutic holidays</span><p id="par0155" class="elsevierStylePara elsevierViewall">ALN discontinuation after only two years of administration in the high bone turnover population does not seem a good therapeutic option, as a study conducted in postmenopausal women aged 40–60 years showed that ALN (20<span class="elsevierStyleHsp" style=""></span>mg/day) administered for 2 years prevents BMD loss.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">24</span></a> However, after discontinuation, the rate of bone loss in postmenopausal women is recovered.</p><p id="par0160" class="elsevierStylePara elsevierViewall">On the other hand, we have comparative data regarding maintaining ALN for 5 years versus 7 years in a study of postmenopausal women with osteoporosis (mean age 63 years), in which the administration of ALN 10<span class="elsevierStyleHsp" style=""></span>mg/day for 7 years produced a sustained BMD increase in the lumbar spine and femoral neck.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> However, women who discontinued ALN treatment for 2 years after 5 years of administration (20<span class="elsevierStyleHsp" style=""></span>mg/day for the first 3 years and 5<span class="elsevierStyleHsp" style=""></span>mg/day for the following 2 years) remained stable in lumbar spine BMD and decreased BMD in the femoral neck, although not significantly. This same study showed that the treatment with ALN during 7 years kept the bone formation and resorption markers reduced and stable, while drug discontinuation for 2 years after 5 of administration resulted in a slight increase in both, resorption as well as formation markers.</p><p id="par0165" class="elsevierStylePara elsevierViewall">The data at 10 years of the same population of the previously mentioned study confirmed that the group of 86 women who continued treatment with ALN for 10 years still gained bone mass in the lumbar spine and, to a lesser degree, in the femoral neck, while the group of women who discontinued treatment with ALN for 5 years after having received it for another 5 kept a stable spine BMD and lost bone mass in the femoral neck (2.4% in 5 years).<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> An interesting fact was that the incidence of morphometric vertebral fractures, collected as an adverse event, did not increase in the group who discontinued treatment for 5 years. However, the number of patients is too small to find significant differences.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Long-term treatment with bisphosphonates</span><p id="par0170" class="elsevierStylePara elsevierViewall">Initially, the <span class="elsevierStyleItalic">American Society for Bone and Mineral Research</span> (ASBMR), following a review of the possible side effects of BP, and giving special attention to AFF, makes the following recommendations<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a>:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0175" class="elsevierStylePara elsevierViewall">Little is known about the optimal duration of treatment with BP.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0180" class="elsevierStylePara elsevierViewall">Patients with osteoporosis treated with ALN and RSN will benefit from their anti-fracture effect for at least 5 years.</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0185" class="elsevierStylePara elsevierViewall">However, continued treatment with BP beyond 5 years should be re-evaluated annually, investigating factors such as BMD (especially the hip), history of previous fracture, concurrent diseases or drug-induced osteopenia, and being alert to new data in a rapidly changing field.</p></li></ul></p><p id="par0190" class="elsevierStylePara elsevierViewall">In light of these observations, the ASBMR proposed an algorithm to be applied in patients who are treated with BP for 5 or more years (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). A change of therapeutic target should be considered if the patient qualifies as a high risk subject, either because there were multiple previous fractures or because fractures occurred during the antiresorptive therapy. BP withdrawal and annual reassessment is recommended in patients classified as low-risk. The main question lies in the intermediate-risk patients (without multiple fractures, without fractures during treatment, but with a low BMD in hip and/or any fracture associated risk factors), with whom continued BP treatment is recommended, reassessing the patient annually.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">In 2011, the <span class="elsevierStyleItalic">Food and Drug Administration</span> created a committee to review the efficacy and safety of long-term use of BP and established the following recommendations:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">•</span><p id="par0200" class="elsevierStylePara elsevierViewall">Reassess the need to continue treatment with BP in patients who have received treatment for a period of 3–5 years (because they are the follow-up periods of the reference trials) and assess the possibility of therapeutic holidays.</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">•</span><p id="par0205" class="elsevierStylePara elsevierViewall">Withdrawing treatment is not recommended in patients at high risk. Therapeutic holiday indication is set according to the individual's risk.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a></p></li></ul></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Restarting treatment after therapeutic holidays</span><p id="par0210" class="elsevierStylePara elsevierViewall">There is no consensus on when to restart the treatment (or which drug). Periodic reassessments are recommended, restarting treatment whenever a new fragility fracture occurs, when there is a significant BMD loss or when significant BRM changes appear. An alternative is to re-evaluate treatment reintroduction using FRAX<span class="elsevierStyleSup">®</span><a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a> and BMD. A biannual follow-up with BMD and FRAX<span class="elsevierStyleSup">®</span> should be done if treatment reintroduction is not indicated.</p><p id="par0215" class="elsevierStylePara elsevierViewall">Other factors to consider are: type of BP administered, fracture risk factors, history of previous fractures, BMD and age of the patient.</p><p id="par0220" class="elsevierStylePara elsevierViewall">Based on the affinity that each BP has for bone tissue, different time periods have been proposed for therapeutic holidays, as expressed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0225" class="elsevierStylePara elsevierViewall">A recently published work suggested the type of follow-up to be implemented in these patients during the therapeutic holidays: it proposes to perform DXA and BRM determination every 1–2 years. Depending on the results, treatment would resume if a decrease higher than 3–5% in BMD (according to location) or an increase higher than 25–30% in BRM is observed.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0230" class="elsevierStylePara elsevierViewall">Patients with indication of treatment for osteoporosis will usually need it for many years, exceeding the proven safety periods of each drug.</p><p id="par0235" class="elsevierStylePara elsevierViewall">Due to the occurrence of side effects or loss of efficacy, it seems reasonable that the patient will need to use different treatment choices throughout his/her life. There is no clear guidance on how to plan the treatment, having to individualize it according to medical characteristics and patient preferences.</p><p id="par0240" class="elsevierStylePara elsevierViewall">Generally, it is recommended to use treatments that go from low to high antiresorptive potency, leaving the most potent drugs for older ages, where the risk of fracture is higher.</p><p id="par0245" class="elsevierStylePara elsevierViewall">BPs are potent antiresorptive drugs capable of reducing the risk of fracture, with pharmacokinetic characteristics and behaviour that anticipate an anti-fracture effect during several years after withdrawal.</p><p id="par0250" class="elsevierStylePara elsevierViewall">The term “therapeutic holidays” refers to a temporary interruption of the osteoporosis treatment with BP, reintroducing it after a period of rest.</p><p id="par0255" class="elsevierStylePara elsevierViewall">The molecular differences between the different types of BPs gives them a different affinity for bone tissue, this determines the length of the therapeutic holiday, according to each type. Thus, the rest period would be one-year maximum for RSN, between 1–2 years for ALN and 2–3 years for ZLN.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of interests</span><p id="par0260" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres640220" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec654274" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres640219" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec654273" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Concept of therapeutic holidays" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Pharmacokinetics of bisphosphonates" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Differences between bisphosphonate agents" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "Comparison of the efficacy of continued treatment with bisphosphonates versus therapeutic holidays" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Maintenance versus alendronate suspension" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Maintenance versus suspension of risedronate" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Maintenance versus suspension of zoledronate" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Maintenance versus suspension of ibandronate" ] ] ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Selecting patients for therapeutic holidays" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Long-term treatment with bisphosphonates" ] 11 => array:2 [ "identificador" => "sec0060" "titulo" => "Restarting treatment after therapeutic holidays" ] 12 => array:2 [ "identificador" => "sec0065" "titulo" => "Conclusions" ] 13 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interests" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-03-11" "fechaAceptado" => "2015-03-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec654274" "palabras" => array:4 [ 0 => "Osteoporosis" 1 => "Bisphosphonates" 2 => "Antiresorptive treatment" 3 => "Therapeutic holidays" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec654273" "palabras" => array:4 [ 0 => "Osteoporosis" 1 => "Bifosfonatos" 2 => "Tratamiento antirresortivo" 3 => "Vacaciones terapéuticas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Oral bisphosphonates (BFs) are drugs widely used in the treatment of osteoporosis and placed as first-line treatment for osteoporosis in most clinical guidelines. BFs are effective drugs that reduce the incidence of fractures and even reduce mortality. Because of their great affinity for bone, BFs have shown that even when they are discontinued still offer a latent protective effect on bone mineral density, maintaining their anti-fracture effect.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">However, prolonged use for years has been linked to the gradual emergence of complications such as osteonecrosis of the jaw or atypical femur fractures, which have raised questions as when to hold and when to make a final or temporary break, recognized as periods of rest or “therapeutic holidays” of these drugs.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Thus, in patients treated with BF for a period of 3–5 years with a low risk of fracture, the drug should be discontinued and restarted when there is an indication for treatment. In contrast, in patients with moderate risk, therapeutic holidays are advised, while reassessing after 2–3 years for restarting purposes. Finally, in patients with high risk of fracture, treatment with BF should not be withdrawn.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Los bifosfonatos (BF) orales son fármacos ampliamente utilizados en el tratamiento de la osteoporosis y se sitúan como primera línea de tratamiento para la osteoporosis en la mayoría de las guías clínicas. Son fármacos eficaces que reducen la aparición de fracturas e incluso disminuyen la mortalidad. Debido a su gran afinidad por el tejido óseo, los BF han demostrado que, incluso cuando se interrumpe su administración, siguen ofreciendo un efecto protector sobre la densidad mineral ósea e incluso sobre la aparición de nuevas fracturas.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Sin embargo, su uso prolongado durante años se ha relacionado con la aparición de algunas complicaciones, como la osteonecrosis mandibular o las fracturas atípicas de fémur, que han cuestionado la duración del tratamiento con estos fármacos y abierto la posibilidad de realizar interrupciones, definitivas o temporales, reconocidas como «vacaciones terapéuticas».</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Así, en pacientes tratados con BF durante un período de 3 a 5 años con riesgo bajo de fractura, se aconseja retirar el fármaco y reiniciarlo cuando vuelva a presentar indicación de tratamiento. En cambio, en pacientes con riesgo moderado, se aconseja realizar vacaciones terapéuticas y reevaluar a los 2-3 años para reiniciar el tratamiento. Por el contrario, en aquellos pacientes con riesgo elevado de fractura no debería retirarse el tratamiento.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Moro Álvarez MJ, Neyro JL, Castañeda S. Vacaciones terapéuticas en osteoporosis: estrategia en el tratamiento a largo plazo con bifosfonatos. Med Clin (Barc). 2016;146:24–29.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1909 "Ancho" => 2522 "Tamanyo" => 337342 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Molecular differences between bisphosphonates confer a different affinity for hydroxyapatite and different antiresorptive potency.</p>" ] ] 1 => array:9 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Modified from Shane et al.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1375 "Ancho" => 1625 "Tamanyo" => 141016 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Algorithm proposed by the <span class="elsevierStyleItalic">American Society for Bone and Mineral Research</span> for the therapeutic management of patients who have undergone bisphosphonate treatment for 5 years or more.</p> <p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">BP: bisphosphonate; FN: femoral neck; BMD: bone mineral density; Fx: fracture; BRM: bone remodelling markers.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Modified from Diab and Watts.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a>" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Duration of therapeutic holidays \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rationale for holidays: bone affinity \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Risedronate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">One year \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Alendronate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Between one and two years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intermediate \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Zoledronate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Between 2 and 3 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1053351.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Recommendations regarding duration and rationale for considering bisphosphonate therapy holidays.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0150" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.M. 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