Compliance, Persistence, and Preferences Regarding Osteoporosis Treatment During Active Therapy or Drug Holiday

Adherence Compliance, Persistence, and Preferences Regarding Osteoporosis Treatment During Active Therapy or Drug Holiday The Journal of Clinical Pharmacology 2016, 0(0) 1 7 C 2016, The American College of Clinical Pharmacology DOI: 10.1002/jcph.738 Alona Eliasaf, PharmD 1, Alina Amitai, PharmD 1, Mira Maram Edry, MD 2, Shimona Yosselson Superstine, PharmD, MPH 3, and Pnina Rotman Pikielny, MD 4 Abstract Osteoporosis treatments reduce the risk of fractures by 30% 50%, but adherence after 1 year is only about 50%. Drug holiday, a period with no active treatment, is part of routine management. The objective of this study was to determine compliance and persistence with osteoporosis therapy among postmenopausal women and to assess attitudes regarding treatment resumption among patients on drug holiday. This was a prospective observational study of patients followed at a dedicated metabolic bone clinic September 2013 February 2014. Compliance was assessed by medication possession ratio (MPR; number of doses dispensed relative to the number prescribed). Persistence was defined as continuation of treatment without a >30-day gap in prescription refills. Of 150 patients (70.1 ± 8.1 years), 57% were prescribed a medication: 64% oral, mostly bisphosphonates. MPR 80% was found in 80% and <50% in 12%; it was 100% for zoledronic acid and denosumab and 97%, 85%, 83%, and 70% for raloxifene, teriparatide, oral bisphosphonates, and strontium ranelate, respectively. Of 39 patients prescribed oral bisphosphonates, 77% persisted with treatment, and 89% took them as directed. Of 64 patients on a drug holiday, 59% expressed confidence in their physician s future treatment choice, whereas 19% expressed concerns about resuming treatment. Compliance among patients attending a dedicated bone clinic was higher than that reported in the literature. High persistence and compliance may be specific to patients followed in this type of setting. This study provides new information about attitudes of patients on a drug holiday. Most were not concerned about resuming treatment and did not have a preferred medication. Keywords osteoporosis treatment, compliance, persistence, preferences, drug holiday Osteoporosis is a systemic bone disease characterized by decreased bone strength and increased risk of fractures. The disease is common among the elderly and in postmenopausal women. The decline in bone strength is the result of low bone mass and structural deterioration of bone tissue. Fractures are associated with morbidity and mortality and poorer quality of life. 1 It is estimated that about 10 million Americans older than age 50 have osteoporosis, and approximately 34 million are at risk of getting the disease. 2 These huge numbers create a heavy financial burden on the health care system. 3,4 In Israel, the prevalence of osteoporosis among women older than age 65, according to self-reports, is about 28%. 5 Osteoporosis treatment includes oral or injectable drugs with various dosing frequencies, including bisphosphonates, raloxifene, teriparatide, strontium ranelate, and denosumab. 1,6 Individual treatment is determined clinically, based on patient history, drug properties, and reimbursement policies. Recently, stopping bisphosphonate treatment after several years has become part of the treatment regimen. The rationale behind this drug holiday is the prolonged half-life of bisphosphonates in bone tissue, as well as lack of proven efficacy of treatment beyond 10 years. Treatment reinitiation is based on bone mineral density, bone turnover markers, and clinical evaluation. 7 In clinical trials, treatments for osteoporosis have been shown to reduce the risk of fractures by 30% 50%. 6,7 However, it seems that this efficacy may not be replicated in a real-world setting because of poor compliance. 8 Previous data have shown that approximately 50% of patients discontinue treatment within 1 year, with most discontinuations occurring within 1 Division of Clinical Pharmacy, Pharmacy Services, Meir Medical Center, Kfar Saba, Israel 2 Hospital Administration Department, Meir Medical Center, Kfar Saba, Israel 3 Division of Clinical Pharmacy, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel 4 Bone Health Service, Endocrine Department, Meir Medical Center, Kfar Saba, Israel, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Submitted for publication 4 February 2016; accepted 14 March 2016. Corresponding Author: Pnina Rotman-Pikielny, MD, Department of Endocrinology, Meir Medical Center, 59 Tschernihovsky St., Kfar Saba, Israel 44281 Email: pnina.rotman@clalit.org.il

2 The Journal of Clinical Pharmacology / Vol 0 No 0 2016 the first few months. 9,10 Low compliance and persistence to treatment lead to increased risk of fractures. Women with poor (less than 50%) refill compliance receive almost no benefit from bisphosphonate treatment, whereas those with more than 50% refill compliance receive progressively increasing benefit from the drugs up to the maximum compliance level, which is above 80%. 11 Poor medication compliance results from a variety of factors, including complicated administration instructions, concerns about side effects, cost of treatment, and misunderstanding the consequences of noncompliance. 12 Some evidence supports the notion that less frequent administration improves patient compliance. 13 15 The current study examined compliance and persistence rates with osteoporosis therapy among postmenopausal Israeli women treated at a metabolic bone clinic. Compliance and persistence based on selfreports and on medications issued according to a computerized database were evaluated. Reasons for noncompliance were assessed, and intermedication differences were evaluated. Another issue that, to the best of our knowledge, is investigated here for the first time is patients preferences and concerns about resumption of treatment after a drug holiday. Understanding the extent of the adherence problem to osteoporosis drug therapy, as well as possible reasons for low compliance, could provide the basis for strategies to improve adherence to treatment and reduce the risk of fractures. Methods The study was approved by the Institutional Review Board of Meir Medical Center. All the patients provided verbal consent to participate in the study and agreed to answer the questionnaire. Patient Population The study population included postmenopausal Israeli women treated at a metabolic bone clinic between September 2013 and February 2014 who met the inclusion criteria. Eligible patients were women with a diagnosis of osteoporosis who received at least 1 prescription for an osteoporosis drug in the previous 5 years. All participants were current members of Clalit Health Services (CHS) health maintenance organization (HMO), the largest HMO in Israel, with more than 4.2 million insured members. Meir Medical Center is an 800-bed, university-affiliated secondary referral center that serves a population of about 1 million and belongs to Clalit HMO. The Bone Clinic was established in 2006 and has been directed by a single senior endocrinologist. It serves about 1400 patients annually. Most referrals to the clinic are initiated by local family physicians and also by physicians from other disciplines such as orthopedic surgeons, rheumatologists, pulmonologists, and gastroenterologists. Data Collected by Personal Interviews Eligible patients were identified by reviewing the medical records of all patients invited to the outpatient Bone Clinic. Data were collected by a clinical pharmacist, who interviewed patients before a routine doctor s visit. The interviews were conducted after explaining the aims of the study and obtaining verbal consent to participate. The participants were asked to reply to a short questionnaire about osteoporosis medication use. They were asked if they were taking or had discontinued drug therapy. If they were taking medication, information about the type of medication, duration, compliance, and use according to instructions was collected. If participants were no longer on active medication therapy, they were asked if it was because of their own or the doctor s decision. Information was collected about the reasons for stopping treatment, preferences and concerns about resuming it, and preferences regarding the frequency of drug administration. Data Collected From the HMO Database Data collected from the computerized medical records included demographics, height and weight, last bone mineral density results, year of osteoporosis diagnosis, history of fractures, and prescription refills for osteoporosis drugs during the past year. Medication Adherence, Compliance, and Persistence Adherence is a general term that encompasses the terms compliance and persistence, but it is sometimes used as a synonym for compliance. 6,16 Although the literature includes many definitions of adherence, we use it as a term that encompasses compliance and persistence. Compliance is defined as the extent to which a patient follows the prescribed interval and dose of a certain medication. 16 It is assessed by the medication possession ratio (MPR), which is calculated by the number of doses dispensed in relation to those prescribed over a period and reported as a percentage. It is easily calculated from computerized databases and considered a reliable parameter. Compliance with a prescription is assumed when medication is dispensed. 16,17 In this study, MPR was calculated for the 12 months prior to study enrollment. Data about drugs dispensed were obtained from the CHS computerized database, which is objective and reliable. MPR calculated from computerized medical databases is a standard method, commonly used to calculate adherence in osteoporosis research. 18 Medication persistence (MP) is defined by the duration of treatment without a gap in refills of more than

Eliasaf et al 3 30 days. 16 Persistence was treated as a dichotomous variable, and patients were described as persistent or nonpersistent. MP was assessed for oral bisphosphonates for the 12 months prior to enrollment. Statistical Analysis Sample Size Calculation. Based on the literature and personal experience of the senior physician specializing in metabolic bone diseases, we assumed that the MPR among patients on oral treatment would be about 10% lower than the MPR for patients receiving injections. 19 21 Therefore, sample size was considered to be 40 patients in each group, for a total sample of 80. We also assumed that 60% of the patients enrolled would be under active treatment for osteoporosis and that 40% would be on a drug holiday, requiring a sample size of at least 140 interviews. Statistical Analysis. Data are presented as number and percentage for nominal variables and as mean, standard deviation, and median for continuous parameters. Continuous variables were tested for normality (Shapiro-Wilk test). Differences in continuous parameters between 2 groups were calculated with a t test or Mann-Whitney nonparametric test, among more than 2 groups by a 1-way analysis of variance or Kruskal-Wallis nonparametric test and between any 2 parameters using Bonferroni post hoc comparison, each when appropriate. Nominal data were analyzed using a chi-square or Fisher s exact test. Pearson or Spearman correlations were calculated, depending on the distribution of the variables. P <.05 was considered statistically significant. All analyses were performed using SPSS-21 software. Results Of 150 women enrolled (mean age, 70.1 ± 8.1 years), 57% were on active drug therapy for osteoporosis, and 43% were on drug holiday. About half the patients had a history of at least 1 osteoporotic fracture, and about a quarter had a history of at least 2 fractures. Average hip t score was 2.1 ± 0.7, and average spine t score was 2.9 ± 1.0. Seventy-five percent of patients were taking calcium and vitamin D supplements (Table 1). Of 86 patients who were on active drug therapy, 64% were prescribed oral medication, mostly a bisphosphonate, and 36% took injectable medications (zoledronic acid, denosumab, and teriparatide). The mean MPR for all drug treatments was 86.9% ± 25.1%. The MPR for strontium ranelate was statistically significantly lower than that for zoledronic acid and denosumab (P =.001). MPR 80% was found in 80% of the treated patients, whereas the MPR was <50% in 12%. Distribution of medications and individual MPRs are shown in Table 2. In addition, compliance with injectable Table 1. Baseline Characteristics of Patients (n = 150) Clinical Parameter All Patients, n (%) or Mean ± SD Demographics Age (y) 70.1 ± 8.1 Age 65(y) 112 (74.7) Age of menopause (y) a 48.2 ± 4.4 BMI (kg/m 2 ) b 25.9 ± 4.4 BMI < 21(kg/m 2 ) 11 (10.8) Duration of treatment (y) Patients on active drug therapy (n = 86) 1.7 ± 1.7 Patients on drug holiday (n = 64) 4.8 ± 3.7 Prior fractures, n (%) At least 1 74 (49.3) At least 2 39 (26) Previous spine fracture 22 (14.6) Previous hip fracture 14 (9.3) Previous Colles fracture 4 (2.7) BMD test results Hip t score c 2.1 ± 0.7 Spine t score d 2.9 ± 1.0 Hip t score 2.5 56 (39.2) Spine t score 2.5 102 (73.4) Concurrent drug/supplement therapy Vitamin D and calcium 112 (74.7) Vitamin D 138 (92) Calcium 120 (80) Gastroprotective agents (PPIs/H 2 blockers) 38 (25.3) Corticosteroids 9 (6) Data are based on a n = 104; b n = 102; c n = 143; and d n = 139. Table 2. Medication Possession Ratio for Drug Therapies in Patients With Osteoporosis Drug All Patients, n = 86 (%) MPR% P a Zoledronic acid 12 (14) 100 ± 0.001 b Denosumab 13 (15) 100 ± 0 Raloxifene 3 (3) 97.4 ± 4.4 Teriparatide 6 (7) 85.5 ± 16.3 Oral bisphosphonates 39 (45) 83.5 ± 28.3 Strontium ranelate 13 (15) 70.5 ± 33.1 Total 86 (100) 86.9 ± 25.1 a P in Kruskal-Wallis. b Bonferroni post hoc comparison: strontium ranelate zoledronic acid and denosumab. drugs was significantly higher than with oral drugs (oral bisphosphonates, raloxifene, and strontium ranelate; P <.0001; data not shown). Older women were more likely to comply with treatment. Women 65 years of age (range, 65 89 years; n = 112) had an MPR of 91.4% ± 18.4% compared with 74% ± 36.1% for younger women (range, 53 64 years; n = 38); P =.004. Other variables such as bone density measurements, previous fractures, and other drug treatments (corticosteroids or gastroprotective agents) were not associated with compliance. Of 39 women who were prescribed oral bisphosphonates, 77% persisted with treatment over the last

4 The Journal of Clinical Pharmacology / Vol 0 No 0 2016 12 months. Of the 35 patients taking oral bisphosphonates, 89% took them as directed, compared with 25% of patients taking strontium ranelate (n = 8). Common errors in oral bisphosphonate treatment included taking the drug at the wrong time of day (n = 3), at the wrong time in relation to food (n = 2), and not remaining upright for a half hour after taking the medication (n= 2). Improper use of strontium ranelate included taking the drug at the wrong time of day (n = 3) and at the wrong time in relation to food (n = 8). Despite physicians orders, 7% of participants decided to stop taking their medications. Reasons for stopping the treatment were presumed side effects (n = 3), concern about side effects (n = 2), uncomfortable dosing frequency (n = 1), and complexity of administration instructions (n = 1). Sixty-four women were on a scheduled drug holiday. Of these, 81% did not express concern about resuming treatment. When asked if they wanted to reinitiate the same drug, most expressed confidence in their physician s treatment choice. Reasons for refusing to resume the previous medication included possible side effects, lack of efficacy, and interference with lifestyle (Table 3). All study participants were asked about their preferences regarding the frequency of the dosing regimen; 57% preferred annual treatment, and 22% preferred monthly treatment over other possibilities such as daily, weekly, or every 6 months. Only 5% preferred to receive treatment every 6 months. Discussion Several studies have investigated compliance and persistence with osteoporosis treatment in different countries. Most dealt with adherence to a single drug or treatment regimen and did not address differences in adherence among drugs. These studies have consistently shown low compliance and persistence to osteoporosis drug therapy, mostly to bisphosphonates, regardless of the specific agent investigated, the route of administration, or the dosing regimen. 11,12,14,16,18 The current study directly compared adherence to diverse osteoporosis treatments in patients from a dedi- Table 3. Opinions Regarding Resuming Previous Medication After a Drug Holiday Opinion All Patients, n = 64 (%) Agree to resume previous drug 8 (13) Will comply with physician s treatment choice 38 (59) Refuse to resume previous drug 18 (28) Reasons for refusal Adverse effects 8 (13) Lack of effectiveness 8 (13) Inconvenient instructions 2 (3) cated bone diseases clinic in Israel. Compliance among the study participants was higher than that reported in the literature. The MPR appeared to be high; however, it was lower for strontium ranelate. Good compliance, MPR 80%, was found in 80% of patients. Good compliance to osteoporosis medications is clinically important because it is associated with lower fracture rates. 11,22 Notably, average treatment duration for patients on active drug therapy was 1.7 ± 1.7 years. In this study, compliance with oral bisphosphonates was good, with an MPR of 83.5%, higher than the 60% to 70% compliance reported in the literature after 1 year of treatment. 18,23 Previous data from Israel reported 66% compliance with oral bisphosphonate treatment 15 ; 77% persisted with treatment for the previous 12 months. Persistence rates to oral bisphosphonates after 1 year of treatment have been shown to be even lower than compliance. 11,14,22 The results of our study are similar to those of a recent report that prospectively assessed compliance and persistence to alendronate therapy among 153 postmenopausal women in Poland. The women were followed for 1 year, with clinic visits every 2 months. The compliance rate, assessed as percentage of patients continuing treatment, was 95%. The authors concluded that good adherence depends on frequent monitoring. 24 Similar data were found in Canada. The Canadian Database of Osteoporosis and Osteopenia was searched for patients who initiated therapy and found 1196 patients on etidronate, 477 on alendronate, and 294 taking hormone replacement therapy. After 1 year, 90.3% of patients persisted with etidronate and 77.6% with alendronate. These high persistence rates were probably the result of a selected patient population from tertiarycare clinics who received frequent reminders from staff members (nurse educators and physicians). 25 Injectable preparations including teriparatide, denosumab, and zoledronic acid had significantly higher compliance rates compared with oral preparations such as strontium ranelate, raloxifene, and bisphosphonates (P <.0001). These findings are consistent with previous studies and reinforce the common perception that injectable drugs can overcome some of the barriers of oral therapy, such as cumbersome administration instructions and gastrointestinal side effects and improve treatment adherence. 19,20,26,27 Compliance with teriparatide was 85.5%, whereas compliance to denosumab and zoledronic acid was 100%. Teriparatide is given daily to patients with very high fracture risk or to those in whom bisphosphonate therapy has failed. 1 Therefore, we might expect better compliance from patients with more severe disease. In fact, compliance rates of 85% can only be explained by the uncomfortable administration of the drug that includes frequent injections, as another study argued that patients prefer parenteral

Eliasaf et al 5 administration only if the schedule is less frequent than that of conventional oral dosing. 28 Our results indicate that age was a positive predictor of compliance with osteoporosis treatment because age older than 65 years was associated with better compliance (P =.004). These results are consistent with previous studies that documented increased adherence and persistence in older patients until age 75 and may indicate that younger patients are less meticulous with regard to drug treatment, perhaps because they feel less likely to sustain a fracture. 15,24 Administration instructions for bisphosphonates and strontium ranelate may be uncomfortable for patients. Bisphosphonates must be taken after an overnight fast with a glass of water at least 30 minutes before ingesting food, drink, or another medication. Patients are required to avoid a supine position for at least 30 minutes after the dose. These administration instructions are important to assure optimal drug absorption. 1 Strontium ranelate granules for oral suspension should be dispersed in water and taken once daily. Strontium ranelate absorption is reduced by food, and the drug should therefore, be administered between meals. Ideally, it should be taken at bedtime, preferably at least 2 hours after eating. 6 Although the 2 drugs have unique administration instructions, the rates of adherence to instructions differed. Of 35 patients on oral bisphosphonates, 89% took them as directed, compared with 27% of patients taking strontium ranelate appropriately (P <.0001). This difference may be because strontium ranelate is less popular and relatively new in the Israeli market (since 2011); thus, doctors and pharmacists are apparently less familiar with its specific administration instructions. This study examined the preferences and concerns of patients on a drug holiday with regard to resuming treatment. Forty-three percent of study participants were on a scheduled drug holiday, consistent with the current therapeutic approach that includes bisphosphonate treatment cessation after several years for patients with stable disease. This treatment policy is relatively new and, to our knowledge, has not been investigated in depth in previous studies. 1 We found that 81% of the patients on a drug holiday were not concerned about resuming medication, and most did not express a preference for a specific medication. Studies on compliance to drug therapy in chronic diseases identified that doctor patient relationships, communication, and shared decision making that takes into account the patient s health beliefs are important factors affecting compliance. 29 High persistence and compliance rates to diverse osteoporosis drugs and lack of concern about the resumption of treatment may indicate a trusting relationship between doctor and patient in the clinic investigated here. A few studies have shown that patients receiving osteoporosis treatment prefer therapeutic regimens with longer periods between doses. 13,26,30,31 In this study, most patients preferred annual treatment, and only a few chose twice-yearly treatment. In Israel, zoledronic acid (Aclasta) became available in 2008, whereas denosumab (Prolia), a relatively new drug, was launched in 2012. Entry of a drug to public awareness affects its preference. Makita et al from Japan reported that 60% of study participants preferred weekly treatment over daily or monthly dosing. This preference seems to derive from monthly bisphosphonate being a new therapeutic option in Japan at the time of the study. 32 This study had some limitations. First, it was an observational study that investigated female patients with postmenopausal osteoporosis using a self-constructed questionnaire. Conducting the study among patients from a dedicated bone clinic followed by a specialist physician created an inherent selection bias. Because of the small sample size, there were few patients in each drug group. Moreover, compliance and persistence analysis was retrospective and did not provide substantial information on explanatory factors. In addition, it is possible that the present assessment overestimated compliance because the calculation of MPR is based on the assumption that patients take all medications dispensed by the pharmacy. However, the derived measure, MPR, is considered highly specific because it identifies those not consuming the medication. In addition, patients who belong to the CHS HMO are unlikely to obtain the medications from other sources not captured by the database. Another limitation is that calculating MPR for products with less frequent regimens (eg, denosumab or zoledronic acid) can be misleading. Because of the nature of administration, 1 or 2 applications annually, respectively, lead to 100% compliance within the specified time frame. As a result, to assess compliance with these drugs, longer follow-up is needed. Last, although patient preferences regarding frequency of administration were assessed, other important factors such as route of administration, efficacy, side effects, and cost that may influence preferences were not addressed in this study. Conclusions Compliance among postmenopausal osteoporotic patients followed up in a dedicated bone clinic was higher than that reported in the literature. High persistence and compliance rates may be specific to the study population, which included highly motivated patients. It could also have resulted from the unique physician patient relationship and close follow-up every 6 months. This study provides new information about the attitudes of osteoporosis patients toward resuming

6 The Journal of Clinical Pharmacology / Vol 0 No 0 2016 treatment after a drug holiday. The patients on drug holiday were not concerned about resuming medication, nor did they express a preferred choice of drug (previous treatment compared with other treatments). These results indicate that a trusting relationship between doctor and patient seems to be an important factor in medication compliance. Funding The study was not funded. Declaration of Conflicting Interests P.R.P. has received speaker s fees from Eli Lilly, Glaxo Smith Klein, and Merck companies and travel and accommodation fees from Eli Lilly, Glaxo Smith Klein companies. Contributions of Authors Alona Eliasaf conceived of or designed study, performed research, analyzed data, wrote the first draft of the article. Alina Amitai conceived of or designed study, analyzed data, revised the article. Mira Maram Edry analyzed data. Shimona Yosselson Superstine conceived of or designed study, analyzed data, revised the article. Pnina Rotman Pikielny conceived of and designed the study, analyzed data, wrote the first draft of the article. References 1. Watts NB, Bilezikian JP, Camacho PM, et al. AACE Osteoporosis Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2010;16:1 37. 2. Holroyd C, Cooper C, Dennison E. Epidemiology of osteoporosis. Best practice & research. Clin Endocrinol Metab. 2008;22:671 685. 3. Borgström F, Zethraeus N, Johnell O, et al. Costs and quality of life associated with osteoporosis-related fractures in Sweden. Osteoporos Int. 2006;17:637 650. 4. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone and Miner Res. 2007;22:465 475. 5. ICDC. Ministry of Health. National Health Survey in Israel a WHO project, European Sector. EUROHIS. Publication no. 237. Module A: Women s Health; 2004 6. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2013;24:23 57. 7. McClung M, Harris ST, Miller PD, et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am JMed.2013;126:13 20. 8. Sambrook P. Compliance with treatment in osteoporosis patients-an ongoing problem. Aust Fam Physician. 2006;35:135 137. 9. McClung M, Harris ST, Miller PD, et al. Non-compliance: the Achilles heel of anti-fracture efficacy. Osteoporos Int. 2007;18:711 719. 10. Ettinger MP, Gallagher R, MacCosbe PE, et al. Medication persistence is improved with less frequent dosing of bisphosphonates, but remains inadequate. Endocr Pract. 2006;12:522 528. 11. Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc. 2006;81:1013 1022. 12. Gold DT. Understanding patient compliance and persistence with osteoporosis therapy. Drugs Aging. 2011;28:249 255. 13. Emkey R, Koltun W, Beusterien K, et al. Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO). Curr Med Res Opin. 2005;21:1895 1903. 14. Cramer JA, Amonkar MM, Hebborn A, Altman R. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin. 2005;21:1453 1460. 15. Kertes J, Dushenat M, Vesterman JL, Lemberger J, Bregman J, Friedman N. Factors contributing to compliance with osteoporosis medication. Isr Med Assoc J. 2008;10:207 213. 16. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11:44 47. 17. Andrade SE, Kahler KH, Frech F, Chan KA. Methods for evaluation of medication adherence and persistence using automated databases. Pharmacoepidemiol Drug Saf. 2006;15:565 574. 18. Cramer JA, Gold DT, Silverman SL, Lewiecki EM. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int. 2007;18:1023 1031. 19. Ziller V, Zimmermann, SP, Kalder M, et al. Adherence and persistence in patients with severe osteoporosis treated with teriparatide. Curr Med Res Opin. 2010;26:675 681. 20. Ziller,V, Kostev K, Kyvernitakis I, Boeckhoff J, Hadji P. Persistence and compliance of medications used in the treatment of osteoporosis-analysis using a large scale, representative, longitudinal German database. Intl J Clin Pharmacol Ther. 2012;50:315 322. 21. Kendler DL, McClung MR, Freemantle N, Boeckhoff J, Hadji P. Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate. Osteoporos Int. 2011;22:1725 1735. 22. Wade SW, Curtis JR, Yu J, et al. Medication adherence and fracture risk among patients on bisphosphonate therapy in a large United States health plan. Bone. 2012;50:870 875. 23. Imaz I, Zegarra P, Gonzalez-Enriquez J, Rubio B, Alcazar R, Amate JM. Poor bisphosphonate adherence for treatment of osteoporosis increases fracture risk: systematic review and metaanalysis. Osteoporos Int. 2010;21:1943 1951. 24. Sewerynek E, Malkowski B, Karzewnik E, et al. Alendronate 70 therapy in elderly women with post-menopausal osteoporosis: the problem of compliance. Endokrynol Pol. 2011;62:24 29. 25. Papaioannou A, Ioannidis G, Adachi JD, et al. Adherence to bisphosphonates and hormone replacement therapy in a tertiary care setting of patients in the CANDOO database. Osteoporos Int. 2003;14:808 813. 26. Kendler DL, Macarios D, Lillestol MJ, et al. Influence of patient perceptions and preferences for osteoporosis medication on adherence behavior in the Denosumab Adherence Preference Satisfaction study. Menopause. 2014;21:25 32. 27. Migliaccio S, Resmini G, Buffa, et al. Evaluation of persistence and adherence to teriparatide treatment in patients affected by severe osteoporosis (PATT): a multicenter observational real life study. Clin Cases Miner Bone Metab. 2013;10:56 60.

Eliasaf et al 7 28. Fraenkel L, Gulanski B, Wittink D. Patient treatment preferences for osteoporosis. Arthritis Rheum. 2006;55:729 735. 29. Vermeire E, Hearnshaw H, Van Royen P, Denekens J. Patient adherence to treatment: three decades of research. A comprehensive review. J Clin Pharm Ther. 2001;26:331 342. 30. Payer J, Killinger Z, Šulková I, Celec P. Preferences of patients receiving bisphosphonates how to influence the therapeutic adherence. Biomed Pharmacother. 2008;62:122 124. 31. McClung M, Recker R, Miller P, et al. Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate. Bone. 2007;41:122 128. 32. Makita K, Okano H, Furuya T, et al. Survey of the utility of once-monthly bisphosphonate treatment for improvement of medication adherence in osteoporosis patients in Japan. J Bone Miner Metab. 2015;33:55 60.