Osteoporosis International (2019) 30:2155–2165 https://doi.org/10.1007/s00198-019-05104-5 CONSENSUS STATEMENT Determinants, consequences and potential solutions to poor adherence to anti-osteoporosis treatment: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Osteoporosis Foundation (IOF) M. Hiligsmann 1 & D. Cornelissen 1 & B. Vrijens 2 & B. Abrahamsen 3,4,5 & N. Al-Daghri 6 & E. Biver 7 & M.L. Brandi 8 & O. Bruyère 9 & N. Burlet 10 & C. Cooper 11,12 & B. Cortet 13 & E. Dennison 11 & A. Diez-Perez 14 & A. Gasparik 15 & A. Grosso 16 & P. Hadji 17 & P. Halbout 18 & J.A. Kanis 19,20 & J.M. Kaufman 21 & A. Laslop 22 & S. Maggi 23 & R. Rizzoli 7 & T. Thomas 24 & S. Tuzun 25 & M. Vlaskovska 26 & J.Y. Reginster 6,9 Received: 13 June 2019 / Accepted: 18 July 2019 / Published online: 7 August 2019 # The Author(s) 2019 Abstract Summary Many patients at increased risk of fractures do not take their medication appropriately, resulting in a substantial decrease in the benefits of drug therapy. Improving medication adherence is urgently needed but remains laborious, given the numerous and multidimensional reasons for non-adherence, suggesting the need for measurement-guided, multifactorial and individualized solutions. Introduction Poor adherence to medications is a major challenge in the treatment of osteoporosis. This paper aimed to provide an overview of the consequences, determinants and potential solutions to poor adherence and persistence to osteoporosis medication. Methods A working group was organized by the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) to review consequences, determinants and potential solutions to adherence and to make recommendations for practice and further research. A systematic literature review and a face-to-face experts meeting were undertaken. Results Medication non-adherence is associated with increased risk of fractures, leading to a substantial decrease in the clinical and economic benefits of drug therapy. Reasons for non-adherence are numerous and multidimensional for each patient, depending on the interplay of multiple factors, suggesting the need for multifactorial and individualized solutions. Few inter- ventions have been shown to improve adherence or persistence to osteoporosis treatment. Promising actions include patient education with counselling, adherence monitoring with feedback and dose simplification including flexible dosing regimen. Recommendations for practice and further research were also provided. To adequately manage adherence, it is important to (1) understand the problem (initiation, implementation and/or persistence), (2) to measure adherence and (3) to identify the reason of non-adherence and fix it. Conclusion These recommendations are intended for clinicians to manage adherence of their patients and to researchers and policy makers to design, facilitate and appropriately use adherence interventions. Keywords Adherence . Determinants . Osteoporosis . Persistence . Solutions Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00198-019-05104-5) contains supplementary material, which is available to authorized users. Poor or non-adherence to medication remains a major prob- lem in most chronic diseases, including osteoporosis. * M. Hiligsmann Effective and safe medications are available to reduce the risk m.hiligsmann@maastrichtuniversity.nl of fractures [1], but numerous patients do not initiate treatment for osteoporosis or do not take it appropriately, resulting in a Extended author information available on the last page of the article substantial clinical and economic burden [2]. Initiation of 2156 Osteoporos Int (2019) 30:2155–2165 osteoporosis therapy is even poorer than in other disease areas, osteoporosis medications (JYR), the determinants of non- with a substantial decrease in bisphosphonates initiation ob- adherence to osteoporosis medications (MH) and the potential served in the last few years in Europe and the USA [3, 4]. solutions to improve adherence to anti-osteoporosis medica- Investing in medication adherence could improve health out- tions (DC). A group discussion led by MH and ADP followed. comes and health system efficiency [5]. Each participant had the opportunity to comment on the de- Poor or non-adherence with osteoporosis medications is terminants, consequences and potential solutions and then to not a new problem. Several studies have already assessed provide recommendations for practice and further research. the consequences and burden of non-adherence with osteopo- Following this meeting and a symposium that was held at rosis medications being one of the major challenges of suc- the World Congress of Osteoporosis (WCO-IOF-ESCEO con- cessful osteoporosis management [6] and have highlighted the gress, 6 April 2019), members of the writing team (MH, DC, urgency of managing medication adherence. In 2012, a sys- BV, BA, JYR, JK, AG, PH) reviewed a first version of the tematic review of interventions to improve adherence to oste- article drafted by MH; this was then reviewed and commented oporosis medications suggested few high-quality studies and on by all members of the working group. mixed effects of interventions [7]. In recent years, osteoporo- sis management has evolved (e.g. new treatments, new diag- nostic tools, FLS organizations), more interventions to im- Terminology prove adherence have been tested and a better understanding of the determinants of non-adherence is available. In the literature, a number of terms such as ‘adherence’, ‘com- Considering the burden of non-adherence with osteoporo- pliance’, ‘concordance’ and ‘persistence’ have been used to sis medications and the need to provide up-to-date recommen- define how patients take their medicines [9]. In 2012, a col- dations to manage medication adherence, a working group laboration of European research groups in the field of medi- was convened by the European Society on Clinical and cation adherence funded by the European Commission sug- Economic Aspects of Osteoporosis, Osteoarthritis and gested the ABC taxonomy for describing and defining adher- Musculoskeletal Diseases (ESCEO) to review the conse- ence to medications [9], which will be used in this paper. quences and determinants of poor adherence and interventions Adherence to medication is defined as ‘the process by which to manage adherence and improve persistence to osteoporosis patients take their medications as prescribed, composed of A) medication. In addition, this paper aims to provide recommen- initiation, B) implementation and C) discontinuation’ [9, 10]. dations for practice and for further research. Information in- Initiation occurs when the patient takes the first dose of a cluded in this review could be of value to help not only clini- prescribed medication, discontinuation when the patient stops cians to manage adherence of their patients but also for re- taking the medication and implementation is the extent to searchers and policy makers involved in osteoporosis. which a patient’s actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose. Medication persistence is further defined as the length of time between Methods initiation and the last dose, which immediately precedes dis- continuation [9]. Overall, this definition is in agreement with An international working group was formed to review the the definition of the Group for the Respect of Ethics consequences and determinants of poor adherence and inter- Excellence in Science in osteoporosis [11], with the exception ventions, to manage adherence and improve persistence to that implementation has replaced compliance, and initiation is osteoporosis medication and to provide recommendations preferred over primary adherence. for practice and for further research. The working group com- prised clinical scientists, researchers (including experts in ad- herence) and a patient selected by the Scientific Advisory Adherence to osteoporosis medications, Board of ESCEO. clinical and economic consequences In preparation for a working group meeting, a systematic literature review was conducted to identify articles about the In a recent review including 124 studies, the prevalence of determinants and interventions to improve adherence or per- medication adherence ranged from 12.9 to 95.4% [12]. sistence to osteoporosis medications. The literature search was Several studies have reported that initiation, implementation conducted for articles up to December 2018 in PubMed. and persistence to osteoporosis medications are suboptimal. In Further details about the search strategy and inclusion of arti- line with treatment initiation rates in other diseases [13], about cles can be found in Cornelissen et al. [8] 20–30% of patients do not initiate a treatment after a prescrip- A face-to-face meeting then took place on 22 January tion for oral bisphosphonates [14]. In addition, patients on 2019. The meeting started with three short presentations about bisphosphonates frequently miss doses and therefore do not the clinical and economic consequences of non-adherence to implement as prescribed [15]. Persistence rates at 1 year for Osteoporos Int (2019) 30:2155–2165 2157 oral bisphosphonates are commonly estimated between 16 (RR) of 1.16), increased hip fracture risk (RR 1.28) and in- and 60% [16–18], in line with a review of 95 clinical studies creased vertebral fracture risk (RR 1.43). from different disease areas suggesting that about 40% of Studies reporting adherence to osteoporosis medication patients discontinued at 1 year [19]. For example, in a large and its relationship with fracture risk mainly focused on oral observational Belgian study, persistence rates to oral bisphosphonates, although data for other medications (e.g. bisphosphonates were estimated at 39.5% at 1 year, without teriparatide, raloxifene, denosumab or zoledronic acid) also a gap of more of 5 weeks in treatment [20], while only 48% of revealed suboptimal levels [32, 33]. In a large US study, per- patients were adherent (defined as a medical possession ratio sistence to teriparatide and denosumab at 1 year were estimat- (MPR) ≥ 80%). In another study, van Boven et al. showed that ed at 69% and 58% [34]. Non-persistence to denosumab could persistence to weekly oral bisphosphonates was about 60% at further lead to important health problems as discontinuation 1 year and decreased to 25% at 5 years [21], in line with a with denosumab has recently been shown to be associated Danish study [22]. Other studies have even reported that less with rapid bone loss and increased risk of multiple vertebral than 20% were still on treatment as soon as after 12 months fractures [35]. Persistence to yearly intravenous injection of after treatment initiation [23]. Differences in methodologies zoledronic acid is also not convincing, as suggested by a study (e.g. permissible gap to define persistence, adherence mea- that showed that only one-third of patients agreed to a second sures, incorporation of switchers) could explain the differ- administration after 1 year [36]. Furthermore, for some oste- ences between studies and made direct comparison between oporosis medications, persistence to generic formulations has them difficult. been shown to be poorer than for branded formulations [37, Further, osteoporosis remains largely underdiagnosed and 38]. a substantial number of patients at increased risk of fractures A few model-based studies have estimated the economic do not even receive any prescription for osteoporotic therapy consequences of non-adherence at a population level [2, [24] or only calcium and vitamin D supplementation. The 39–42], suggesting important clinical and/or economic impli- osteoporosis treatment gap was estimated between 25 and cations of poor adherence/persistence with osteoporosis med- 95% in European countries [25]. Even in randomised con- ications. For example, poor adherence with osteoporosis med- trolled trials, persistence and adherence with therapy decline ications resulted in about 50% reduction in the potential ben- over time, and any reduced effectiveness caused by subopti- efits observed in clinical trials (in terms of fractures prevented mal adherence is to some extent already captured in clinical and quality-adjusted life-years (QALY)) and a substantial de- trials. terioration of the cost-effectiveness resulting from these med- Different profiles of non-adherent patients could be identi- ications [2, 40]. Medication adherence has further become an fied [26]. Some patients never initiate a treatment, while important factor for inclusion in cost-effectiveness analyses in others delay initiation of therapy. There are patients who fre- osteoporosis [43–45]. Interestingly, economic studies have al- quently miss doses, and multiweek drug holiday periods have so suggested that interventions to improve adherence may also been observed. Several patients further discontinue treat- likely confer cost-effectiveness benefits [43]. Improving ad- ment earlier than prescribed. In a USA study, it was also ob- herence to medication could lead to greater benefits that de- served that among discontinuers, about 45% [27] reinitiated signing a new more effective drug [46]. therapy, with the majority doing so within 6 months of dis- continuation, suggesting that many patients are thus exposed to multiple episodes of starting and stopping of drug actions. Finally, several medication switchers have been reported [28]. Determinants of non-adherence Failure to take account of switchers could distort estimates of adherence and persistence. Adherence is a complex multidimensional phenomenon deter- Poor persistence and adherence to osteoporosis medica- mined by the interplay of several factors. Numerous determi- tions reduce the potential benefits of osteoporosis therapy, nants of non-adherence have been identified in the literature lowering gains in bone mineral density and resulting in in- [12, 47]. The World Health Organization has classified these creased risk of fragility fractures [29]. Two systematic reviews factors into five main categories, i.e. patient-related, therapy- and meta-analyses assessed the impact of adherence/ related, condition-related, health system and socio-economic persistence to oral bisphosphonates on fracture risk. The factors [5]. Recently, Yeam et al. [12] conducted a systematic meta-analysis of Ross et al. [30] indicated that fracture risk literature review up to January 2018 to review and identify increased by approximately 30% with non-adherence (defined factors that influence patients’ adherence to anti-osteoporotic as medical possession ratio < 80%) and by 30 to 40% with therapy. A total of 24 factors and 139 subfactors were identi- non-persistence. Similarly, Imaz et al. [31] reported that low fied from 124 relevant studies. The authors presented types adherence to oral bisphosphonates was significantly associat- and number of studies that presented the case for and against ed with increased non-vertebral fracture risk (relative risk each specific factor and revealed that patient-related factors 2158 Osteoporos Int (2019) 30:2155–2165 were the most commonly studied category followed by effect on treatment initiation with patients who have not pre- therapy-related and condition-related category. viously taken medication being less likely to start [14] while Condition-related factors that were associated with poorer persistence and implementation are generally lower in patients medication adherence included polypharmacy and having on multiple medications [12]. Lau et al. conducted focus gastro-intestinal diseases. History of falls, fractures and groups in Canada to understand reasons for non-adherence screening for osteoporosis were however not associated with and included different patients’ quotes regarding belief in the higher adherence. This is important as patients with a recent importance of taking medications for osteoporosis, fracture are at imminent risk of a further fracture [48]. Patient- medication-specific factors, beliefs regarding medications related factors associated with poorer medication adherence and health, relationships with healthcare providers and infor- included male gender, lower education levels, misconceptions mation exchange [57]. about osteoporosis and lack of perceived benefits of therapy, The patient participating at our working group stressed the whereas higher age was associated with higher medication importance of giving a positive message to the patient and not adherence but only in half of the studies. Among therapy- exaggerating the consequences if the patient does not take the related factors, medication side effects, complex instructions drug. Web and social media nowadays also attract a lot of for medication administration and complex medication regi- attention and could further negatively influence adherence to mens were associated with poorer adherence and lower dosing treatment. frequency with higher adherence, while a history of anti- Reasons for non-adherence are therefore numerous and osteoporosis treatment was not found to be a predictor of multidimensional for the same patient. Each patient’s rea- adherence. Health system-based factors associated with son(s) for non-adherence is different, depending on the inter- poorer medication adherence included care under different play of these multiple factors, and could also change over time medical specialties and lack of patient education (information and be different for each key element of adherence. sharing, counselling from healthcare professional, etc.). Medication adherence is therefore not predictable, suggesting Socio-economic-related factors associated with poorer medi- the need for individualized solutions. cation adherence included current smoking, lower income lev- el and lack of medical insurance coverage [12]. This review did not classify the factors according to adher- Review of interventions ence level, i.e. initiation, implementation and persistence. In another review of systematic reviews that covered 19 disease In 2012, Hiligsmann et al. [7] reviewed and critically appraised areas [47], a total of 771 individual factors of medication interventions to improve adherence and persistence to osteo- adherence were identified of which most were determinants porosis medications. A total of 20 studies tested a patient ad- of implementation, and only 47 determinants of persistence herence intervention and reported quantitative results on ad- with medication and no determinant were specifically provid- herence. Education programs (e.g. written materials, counsel- ed for initiation. In the field of osteoporosis, the patient per- ling, motivational interviewing, combination) were the most ceived need for treatment, patient knowledge, bone density frequent intervention (n = 9). Although patient education im- testing, improved patient-provider relationship, hospitaliza- proved medication adherence in four studies, two large-scale tions and prescription use have been shown to be positively randomized studies reported no benefits [58, 59]. Monitoring/ associated with initiating osteoporotic therapy [49–52]. supervision by bone mineral density or bone turnover markers Reasons for not initiating osteoporotic therapy also include were not shown to be associated with improved adherence. lack of motivation, concern about side effects and medication However, a positive message revealing a good bone turnover costs [52]. Reasons for poor implementation and persistence marker response was associated with a significant improve- with osteoporosis therapy include side effects of treatment, ment in persistence [60]. Simplification of dosing regimens difficulties with medication intake (e.g. 30 min before break- (with and without patient support program), electronic pre- fast), inconvenient dosing regimen, concern about treatment, scription and a pharmacist intervention was associated with no perceived benefits, drug cost, misinformation, insufficient improved adherence but only in couple of studies. motivation or dissatisfaction with their doctor visits [47, For the purpose of this working group, the previous sys- 53–55]. Adherence to osteoporosis medications is simply a tematic review was updated. A description of the literature matter of patient choice, and is due mostly to deliberative search, data and critical appraisal can be found in the article choice [56]. However, reasons for non-adherence can also be of Cornelissen et al. [8]. A total of 15 studies were identified unintentional, resulting from forgetfulness, especially in holi- between June 2012 and December 2018. Very few high- day period [53], and some irrational behaviour could also be quality studies (such as RCTs) were identified, and interven- reported. Factors involved in treatment initiation may further tions were mainly single component intervention. differ than factors involved in persistence or implementation. Interventions were classified as patient education and/or sup- As example, polypharmacy has been shown to have a positive port (n = 9), monitoring and supervision (n = 2), flexible Osteoporos Int (2019) 30:2155–2165 2159 dosing regimen and patient support (n = 3) and interdisciplin- acknowledge that the efficacy of these actions is still largely ary collaboration (n = 1). In each subtype of interventions, unknown and current data could be controversial. mixed results on adherence/persistence were found where Patient education and counselling were shown to improve some studies were shown to be successful and others not post-fracture care and treatment initiation, with more contro- (see next section). Interventions which include counselling versial results on medication adherence. As a prominent ex- with education and/or flexible dosing regimens seem to be ample for post-fracture care, the PREVOST trial suggested most effective, as well as interventions aiming on testing and that repeated oral and written information about fragility frac- initiating medication. tures and osteoporosis management by a case manager in- creased treatment initiation (53% initiated post-fracture care in the intervention compared to 33% in the control) [66]. In Recommendations for practice another study [67], patient education and referral to endocri- nologist by a nurse were shown to improve the initiation of Many factors affect medication adherence. Single interven- calcium and vitamin D, although up to 50% of patients with tions could work but certainly not for all patients. There is osteoporosis did not complete follow-up visits and/or did not not one single intervention to manage adherence. Some rec- adhere to treatment recommendations for osteoporosis. ommendations to improve adherence are made below. Assigning a screening coordinator to identify, educate and It is of primary importance to emphasize the need for treat- follow up with fragility fracture patients and inform their phy- ment adherence and to talk about adherence with patients. To sicians of the need to evaluate bone health was also shown to adequately manage medication adherence, at least three stages increase treatment initiation [68]. A systematic screening are recommended: using FRAX® was also shown to increase use of, and adher- ence to anti-osteoporosis medications in the UK SCOOP Trial 1. What is the adherence problem (initiation, implementa- [69]. In addition, an osteoporosis school program (i.e. four tion and/or persistence)? It is key to identify the ele- classes of 8–12 participants over 4 weeks), peer-led commu- ment(s) of non-adherence problem(s) that you want to nity education and mentorship program or patient education address with the patient(s). program were associated with improved knowledge of osteo- 2. How to measure adherence? Different methods are avail- porosis and initiation of treatment [70]. In a large pragmatic able to measure the elements of medication adherence. randomized controlled trial, however, telephonic motivational Prescription refills and databases are appropriate methods interviewing intervention was not associated with significant to measure initiation and discontinuation of therapy [61] improvements in medication adherence [59]. while electronic monitoring is the preferred method for Adherence monitoring with feedback was also associated implementation, although could be difficult to set up in with improved adherence. Stuurman-Bieze et al. [71] showed real-life settings [61]. The use of self-reports or pill counts that a proactive pharmaceutical care including counselling at could be alternative methods. baseline and at 2 weeks and an active monitoring and counsel- 3. What is the reason and how to fix it? Given the numerous ling every 3 months by pharmacists for patients who should potential factors for non-adherence, it is therefore impor- have redeemed a new prescription leads to improved adher- tant to understand the reason(s) for non-adherence for ence. Ducomlombier et al. [72] further suggests that phone each patient and to find an adequate personalized solution. calls by medical secretaries every 2 months to motivate pa- tients to maintain good adherence to the treatment and to de- These three steps are in line with the Six Sigma framework tect any difficulties in adherence with the prescription using to manage medication adherence developed by Vrijens et al. non-incriminating questions were associated with improved [62]. This framework includes definition (robust taxonomy), adherence. measure (operational definition and performance), analysis Dose simplification including flexible dosing regimen was (understand the cause), addressing the cause and implementing associated with improved adherence. Offering patients a med- solutions and measurement-guided adherence management. ication with less strict administration instructions such as the In addition to the updated systematic review of adherence use of gastro-resistant risedronate tablets that could be taken interventions in osteoporosis, a comprehensive list of inter- after breakfast was associated with improved persistence to ventions is provided with evidence about their effectiveness treatment [73]. Longer dosing regimen (such as 6-month sub- including systematic reviews of adherence interventions in cutaneous injection of denosumab or yearly intravenous injec- other diseases including depression, cardiovascular diseases tion of zoledronic acid) can also be interesting to improve ad- and hypercholesterolaemia [63–65] (Table 1). Patient educa- herence, although adherence levels have also been disappoint- tion and counselling, adherence monitoring with feedback and ed and far from optimal (see previously). Finally, a flexible dose simplification including flexible dosing regimen were dosing regimen (before breakfast; in-between meals; before associated with higher adherence improvements. We however bedtime) was also shown to be associated with improved 2160 Osteoporos Int (2019) 30:2155–2165 Table 1 Evidence about the effectiveness of adherence-enhancing interventions Intervention subclass OP studies Other conditions* Conclusion Education and support Patient education program 4 4 Mixed evidence of effectiveness Patient counselling 1 10 Strong evidence of effectiveness Patient education combined with counselling 11 15 Strong evidence of effectiveness Provision of educational material 2 5 No evidence of effectiveness Monitoring supervision Non-adherence monitoring 1 2 Limited evidence of effectiveness Adherence monitoring combined with counselling 5 10 Strong evidence of effectiveness Drug regimen combined with counselling 1 1 Limited evidence of effectiveness Reminders to take the medication 1 7 Strong evidence of effectiveness Monitoring biomarkers 3 N/a No evidence of effectiveness Dose regimen adjustment and simplification Dose simplification including flexible dosing regimen 4 8 Strong evidence of effectiveness Individual medication program 1 1 Limited evidence of effectiveness Costs covered N/a 1 Limited evidence of effectiveness Other subclasses Combination of interventions mentioned above 3 2 Mixed evidence of effectiveness Other interventions 4 9 Low evidence of effectiveness N/a not applicable *Restricted to depression, cardiovascular diseases and hypercholesterolaemia persistence, although there was no statistical difference in terms evidence, able to discuss complex medical information in a of adherence [74]. manner that is understood by the patient and appropriately con- Improving patient interaction and shared decision-making sider the patient’s expectations, beliefs and concerns [80, 81]. A can also lead to improve treatment initiation and potentially doctor should thus facilitate interaction with the patient and improve adherence. Several guidelines and international him/her, understand the patient’s needs and investigate the type groups recommend that shared decision-making be part of of treatment appropriate for the patients (e.g. dosing regimen). standard treatment. In shared decision-making, both parties share information: the clinician offers options and describes their risks and benefits, and the patient expresses his or her Recommendations for further research preferences and values [75]. Each participant is thus armed with a better understanding of the relevant factors and shares Some areas where further research is needed were identified. responsibility in the decision about how to proceed [75]. First, it is important to improve our understanding on what Decision aids emphasize shared decision-making and include osteoporotic patients want, need and prefer and to better under- several features to support individualized treatment discussions stand how and why patients will (not) be adherent. It is partic- like those needed for fracture prevention. Decision aids for a ularly important to understand the root causes for each aspect of range of conditions have been shown to decrease decisional adherence, i.e. initiation, implementation and persistence. conflict, increase knowledge and (when probabilities are in- Qualitative research is the best way to understand patients’ cluded in the aid) improve the accuracy of risk perception needs and reasons for non-adherence and should be a starting [76]. Some decision aids aiming to facilitate shared decision- point for designing appropriate interventions. Stated preference making in osteoporosis have been designed and shown to im- methods could also be interesting to reveal patients’ preferences prove the quality of clinical decisions about bisphosphonate and important treatment characteristics [82]. therapy and may have improved adherence [77–79]. Second, register-based studies can be attractive to investi- Providing patients with good quality information about os- gate the importance of different factors and identify the stron- teoporosis, their risk and treatment options is needed as a crucial gest and most prevalent risk factors for poor adherence as step to increase the diagnosis and treatment of osteoporosis. targets for intervention. Big (pharmaco-epidemiologic) data The doctor is therefore a key actor to improve medication ad- provide new opportunities to help understand the reasons of herence. As an educator and a partner in making treatment medication non-adherence and may also prove helpful in decisions, the doctor should be familiar with the medical assessing the effects of new initiatives in the area. Osteoporos Int (2019) 30:2155–2165 2161 Third, with a better understanding of patients’ needs and with counselling, adherence monitoring with feedback and non-adherence factors, it would then be possible to design dose simplification including flexible dosing regimen. interventions that fit patients’ needs and wishes on a person- Recommendations for practice and further research were pro- alized manner. It is indeed recommended to develop complex, vided, suggesting the need to emphasize the importance of individualized and multifactorial interventions. There is not adherence to treatment and to talk about adherence with pa- one single intervention to manage adherence. Involving pa- tients, and the need to implement sound measures of adher- tients in the preparation, development and assessment of these ence so that the intervention can be individualized. These complex interventions would be crucial [83]. Further research recommendations are intended for clinicians to manage adher- is also warranted on patient involvement in medication adher- ence of their patients and to researchers and policy makers to ence research and patient empowerment and its role in pro- design, facilitate and appropriately use adherence interven- moting adherence. Complex interventions would thus need to tions and to advance research in the field. be tested in large scale randomized controlled trials. Fourth, as the cost of an adherence intervention may be Acknowledgements The authors are grateful to the Prince Mutaib Chair for Biomarkers of Chronic Disease, King Saud University, Riyadh, KSA high, it would also be important to identify patients that will and the WHO Collaborating Centre for Public Health Aspects of be receptive to interventions and spend our limited resources Musculoskeletal Health and Aging, for its support. on those patients. We further need patient outcome tools to better understand the patient perspective and patient biases in Funding information The meeting was funded by the European Society decision-making concerning osteoporosis therapies [84]. for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). In addition, web-based applications could play a crucial role in supporting patients to improve their adherence to med- ication. Further research focusing on digital adherence inter- Compliance with ethical standards ventions is necessary to determine their value and ideal ways Conflict of interest MLB has received honoraria from Amgen, Bruno to improve osteoporosis medication adherence. Farmaceutici, Kyowa Kirin; academic grants and/or speaker from Other areas for further research include the need to ade- Abiogen, Alexion, Amgen, Bruno, Farmaceutici, Eli Lilly, Kyowa quately communicate about osteoporosis, fracture risk and Kirin, MSD, NPS, Servier, Shire and SPA; and consulting fees from osteoporosis treatment to patients; development of shared Alexion, Bruno Farmaceutici, Kyowa Kirin, Servier and Shire. OB received grants research from Biophytis, IBSA, MEDA, Servier, decision-making; assessment of adherence-management mod- SMB and consulting or lecture fees from Amgen, Biophytis, IBSA, el (such as the three-stage model proposed previously); inno- MEDA, Servier, SMB, TRB Chemedica and UCB. vative methods for monitoring medication adherence; and BC has received Fees for occasional interventions as an expert or policy/healthcare systems initiatives to support adherence speaker for Amgen, Expanscience, Ferring, Lilly, Medtronic, MSD, Mylan, Novartis, Roche Diagnostics and UCB. interventions. CC has received lecture fees and honoraria from Amgen, Danone, Eli Lilly, GSK, Kyowa Kirin, Medtronic, Merck, Nestlé, Novartis, Pfizer, Roche, Servier, Shire, Takeda and UCB outside of the submitted work. Conclusions DC is funded by the Netherlands Organization for Health Research and Development (ZonMw), grant application number 848016001. ED has received honoraria from Pfizer and UCB. Osteoporosis represents a significant healthcare burden in ADP has received consulting and speaker fees from Amgen, UCB, Eli European countries which, due to increasing life expectancies, Lilly, Roche and Gilead and own shares of Active Life Sci. is predicted to increase further in the future [24]. Despite the JAK reports grants from Amgen, Eli Lilly and Radius Health and consulting fees from Theramex. increasing burden and the availability of effective treatments PH has received consulting and speaker fees from Amgen, Dr. in reducing the risk of fractures, most patients are not taking Kade/Besin, Gedeon Richter, Elli Lilly, Meda/Mylan, Novartis, Pfizer, their medication appropriately or do not even start an osteo- Roche, Theramex and UCB and has given expert testimony on behalf porosis medication. Improving treatment initiation and adher- of Novartis. RR has been speaker bureau or member of scientific advisory boards ence to therapy is therefore urgently needed to leverage in full for Danone, Echolight, Effryx, Mylan, Nestlé, ObsEva, Pfizer, Radius the benefits of drug therapy. Health, Sandoz and TEVA/Theramex. Poor and non-adherence with medication is common with a TT reports personal fees for lectures and expertises from Abbvie, treatment gap estimated between and 95% in European coun- Amgen, Arrow, BMS, Chugai, Expanscience, Gilead, HAC-Pharma, LCA, Lilly, Medac, MSD, Pfizer, Theramex, Thuasne, TEVA and UCB tries [25] and about half of the patients discontinuing therapy and financial support or fees for research activities from Amgen, Bone within 1 year. Reasons for non-adherence are numerous, di- Therapeutics, Chugai, HAC-Pharma, MSD, Novartis, Pfizer and UCB. verse and multidimensional, depending on the interplay of JYR has received consulting fees or paid advisory boards from IBSA- multiple factors and may be different for each key element GENEVRIER, Mylan, Radius Health, Pierre Fabre; lecture fees when speaking at the invitation of sponsor for IBSA-GENEVRIER, Mylan, of adherence. Few single interventions have been shown to CNIEL and Dairy Research Council; and grant support from industry improve adherence or persistence to osteoporosis treatment. (all through institution) from IBSA-GENEVRIER, Mylan, CNIEL and Potentially, promising interventions include patient education Radius Health. 2162 Osteoporos Int (2019) 30:2155–2165 The other authors have no conflict of interest to declare relevant to the 14. Reynolds K, Muntner P, Cheetham TC, Harrison TN, Morisky DE, content of this study. Silverman S, Gold DT, Vansomphone SS, Wei R, O’Malley CD (2013) Primary non-adherence to bisphosphonates in an integrated Open Access This article is distributed under the terms of the Creative healthcare setting. Osteoporos Int 24(9):2509–2517 Commons Attribution-NonCommercial 4.0 International License (http:// 15. Rabenda V, Reginster JY (2010) Overcoming problems with adher- creativecommons.org/licenses/by-nc/4.0/), which permits any ence to osteoporosis medication. Expert Rev Pharmacoecon noncommercial use, distribution, and reproduction in any medium, Outcomes Res 10(6):677–689 provided you give appropriate credit to the original author(s) and the 16. Rabenda V, Hiligsmann M, Reginster JY (2009) Poor adherence to source, provide a link to the Creative Commons license, and indicate if oral bisphosphonate treatment and its consequences: a review of the changes were made. evidence. Expert Opin Pharmacother 10(14):2303–2315 17. 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Osteoporos Int 30(3):649–658 oporosis: can we explain why patients do not take their osteoporosis 74. Oral A, Lorenc R, Investigators F-AS (2015) Compliance, persis- medications? Current Osteoporosis Reports 16(6):772–774 tence, and preference outcomes of postmenopausal osteoporotic women receiving a flexible or fixed regimen of daily risedronate: Publisher’s note Springer Nature remains neutral with regard to a multicenter, prospective, parallel group study. Acta Orthop jurisdictional claims in published maps and institutional affiliations. Traumatol Turc 49(1):67–74 Affiliations M. Hiligsmann 1 & D. Cornelissen 1 & B. Vrijens 2 & B. Abrahamsen 3,4,5 & N. Al-Daghri 6 & E. Biver 7 & M.L. Brandi 8 & O. Bruyère 9 & N. Burlet 10 & C. Cooper 11,12 & B. Cortet 13 & E. Dennison 11 & A. Diez-Perez 14 & A. Gasparik 15 & A. Grosso 16 & P. Hadji 17 & P. Halbout 18 & J.A. Kanis 19,20 & J.M. Kaufman 21 & A. Laslop 22 & S. Maggi 23 & R. Rizzoli 7 & T. Thomas 24 & S. Tuzun 25 & M. Vlaskovska 26 & J.Y. Reginster 6,9 1 6 Department of Health Services Research, CAPHRI Care and Public Chair for Biomarkers of Chronic Diseases, Biochemistry Health Research Institute, Maastricht University, P.O. Box 616, 6200 Department, College of Science, King Saud University, MD Maastricht, the Netherlands Riyadh, Saudi Arabia 2 7 Research and Development, AARDEX Group and Department of Division of Bone Diseases, Geneva University Hospitals and Faculty Public Health, University of Liège, Liege, Belgium of Medicine, Geneva, Switzerland 3 8 Open Patient Data Explorative Network, Institute of Clinical FirmoLab, Fondazione FIRMO e Università di Firenze, Resesarch, University of Southern Denmark, Odense, Denmark Florence, Italy 4 9 Department of Medicine, Holbæk Hospital, Holbæk, Denmark Division of Public Health, Epidemiology and Health Economics, 5 Liège, Belgium and WHO Collaborating Centre for Public Health NDORMS, University of Oxford, Oxford, UK Osteoporos Int (2019) 30:2155–2165 2165 18 Aspects of Musculoskeletal Health and Aging, University of Liège, International Osteoporosis Foundation, Nyon, Switzerland Liege, Belgium 19 Centre for Metabolic Bone Diseases, University of Sheffield 10 Global Head of Patient Insights Innovation, Patient Solution Unit, Medical School, Sheffield, UK Sanofi, Lyon, France 20 Mary McKillop Health Institute, Catholic University of Australia, 11 MRC Lifecourse Epidemiology Unit, Southampton General Melbourne, Australia Hospital, University of Southampton, Southampton, UK 21 Department of Endocrinology, Ghent University Hospital, 12 NIHR Musculoskeletal Biomedical Research Unit, University of Ghent, Belgium Oxford, Oxford, UK 22 Scientific Office, Austrian Federal Office for Safety in Health Care, 13 Department of Rheumatology and EA 4490, University-Hospital of Vienna, Austria Lille, Lille, France 23 CNR Aging Branch-NI, Padua, Italy 14 Musculoskeletal Research Unit, IMIM-Parc Salut Mar, CIBERFES, 24 Department of Rheumatology, Hôpital Nord, CHU Saint-Etienne, Universitat Autònoma de Barcelona, Barcelona, Spain Saint-Etienne and INSERM U1059, Université de Lyon-Université 15 Department of Public Health, University of Medicine, Pharmacy, Jean Monnet, Saint-Etienne, France Science and Technology of Targu Mures, Targu Mures, Romania 25 Department of Physical Medicine and Rehabilitation, Cerrahpaşa 16 Patient partner, Geneva, Switzerland Medical Faculty, İstanbul University Cerrahpaşa, Istanbul, Turkey 17 26 Frankfurt Centre of Bone Health, Frankfurt, Germany & Philips- Medical Faculty, Department of Pharmacology, Medical University University of Marburg, Marburg, Germany Sofia, Sofia, Bulgaria