Advertisement

Aging Clinical and Experimental Research

, Volume 31, Issue 11, pp 1541–1547 | Cite as

Retrospective evaluation of persistence in osteoporosis therapy with oral bisphosphonates in Italy: the TOBI study

  • Stefano GonnelliEmail author
  • Carla Caffarelli
  • Giulia Letizia Mauro
  • Ombretta Di Munno
  • Nazzarena Malavolta
  • Silvia Migliaccio
  • Ranuccio Nuti
Original Article

Abstract

Summary

The patients’ persistence with osteoporosis treatments is low. This retrospective, multicenter survey showed that almost 30% of osteoporotic patients discontinued the treatment within the first 6 months and that those taking drinkable bisphosphonates were less likely to interrupt the therapy; instead, the use of generic bisphosphonates was associated to a more precocious interruption.

Purpose

Low persistence with osteoporosis medications is associated with higher fracture risk. This study aimed to assess the persistence to treatment with oral bisphosphonates among Italian osteoporotic patients under treatment for at least 6 months and to evaluate whether the different oral formulations of bisphosphonates may influence the interruption of the therapy.

Methods

723 consecutive osteoporotic patients, aged 50 years or over, referred as outpatients for a follow-up visit after receiving a prescription of an oral bisphosphonate for the first time for at least 6 months were enrolled in this retrospective, multicenter survey carried out under conditions of usual clinical practice. All the patients enrolled were submitted to a standardized interview.

Results

191 patients turned out to have discontinued treatment (28.7%), the more common causes for interruption being the adverse events (43.9%), fear of adverse events (23.3%) and perceived absence of efficacy of the treatment (15.8%). The osteoporotic patients taking drinkable bisphosphonate or on treatment with aromatase inhibitors or under the age of 70 years were less likely to interrupt the treatment. However, these associations were no longer significant when the pharmaceutical formulation (generic vs branded) was included into the multivariate logistic regression model.

Conclusion

This study suggests that the new drinkable formulations of bisphosphonates could be an interesting option able to reduce upper GI adverse events, thus increasing persistence; whereas the generic formulations of bisphosphonates were associated to a premature discontinuation.

Keywords

Osteoporosis Oral bisphosphonates Persistence Drinkable bisphosphonates Generic drug 

Introduction

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and in susceptibility to fracture [1]. Osteoporotic fractures, especially those of the vertebrae and proximal femur, are responsible for a significant increase in mortality, morbidity and economic costs [2]. Therefore, with the progressive aging of the population, osteoporosis and fragility fractures are becoming a problem of crucial importance from both the health and socio-economic point of view.

Several effective drugs are currently available for the treatment of osteoporosis, and many double-blind randomized clinical trials have consistently demonstrated the efficacy of these drugs in reducing the risk of both peripheral and vertebral fractures.

Among these, oral bisphosphonates are the most common first-line treatment for osteoporosis and reduce the incidence of vertebral fractures by 40–50% and of non-vertebral fractures by 20–40% [3]. The interventions proposed to improve medication adherence in osteoporosis have been recently systematically reviewed by Hiligsmann et al. [4]; simplification of dosing regimens may help to improve adherence and persistence. However, as in any other chronic diseases, low adherence is a common clinical problem [4]. It has been reported that less than 70% of women with osteoporosis actually start the prescribed treatment; among those who start, about 50% discontinue it within 1 year; and among those who persist, only a minority fully respects the prescribed regimen (times and doses) [5]. Other studies have found that the adherence to oral bisphosphonates ranges between 40 and 60% and appears to be worse in patients treated with generic medications [5, 6, 7]. The chronic nature of osteoporosis means that long-term treatment is required. Therefore, poor compliance with and low persistence of the use of osteoporosis medications may lead to higher fracture rates and consequently higher medical costs; whereas, better adherence is associated with lower fracture rates and costs [8, 9, 10].

Over the years, several strategies have been proposed aimed at improving adherence to oral bisphosphonate therapy but achieving modest results. In particular, therapeutic interventions aimed to improve medication-related behavior of osteoporotic patients have often failed [4, 11, 12]. Also, the availability of once-a-week and, later, once-a-month formulations, currently used by most patients, does not seem to have led to a substantial increase in compliance and persistence [4].

Since the gastro-intestinal (GI) side effects are one of the most frequent causes of interruption of bisphosphonate therapy, in recent years’ efforts were made to develop alternative formulations for oral administration of bisphosphonates, with the goal of increasing GI tolerability and consequently adherence. At present, both a drinkable formulation and effervescent tablets of alendronate are on the market [13, 14, 15].

The aim of the present study was twofold: first, to assess the persistence to treatment with oral bisphosphonates among Italian osteoporotic patients under treatment for at least 6 months; secondly, to evaluate the causes of interruption of therapy with particular attention to the role of adverse events.

Materials and methods

Study population

The therapy with oral bisphosphonates in Italy (TOBI) study was a retrospective, multicenter survey carried out under conditions of usual clinical practice, in osteoporotic Italian patients (men and women) aged 50 years or over.

A total of 16 Italian outpatient Centres (Departments of Internal Medicine, Rheumatology, Rehabilitation and Geriatrics), participating in the Italian Group for the Study of Bone Metabolism (GISMO) and distributed over all the national territory and located in both academic and non-academic general hospitals were invited to participate to the study.

In each centre, between January and September 2017, experienced clinicians recruited up to 50 consecutive osteoporotic patients, aged 50 years or over, referred as outpatients for a follow-up visit after receiving a prescription of an oral bisphosphonate for the first time for at least 6 months.

Exclusion criteria were the presence of malignancies, multiple myeloma, Paget’s disease of bone, hyperparathyroidism, history of alcohol abuse (> 400 g/week), severe hearing or visual impairment, cognitive problems which would prevent reliable participation to the study, any history of fragility fractures in the last 12 months and or inability to give valid informed consent.

Study protocol was prepared according to the Declaration of Helsinki and subsequent integrations. Written consent was obtained from all participants, and the study was approved by the local Ethical Committee of each centre.

Methods

The patients enrolled were submitted to a standardized interview. The case report included questions related to age, height and weight, lifestyle (smoking habits, alcohol consumption), patient’s history (fractures after the age of 50 years, family history of osteoporosis, family history of fragility fractures, age and type of menopause), concomitant use of specific drugs (namely, glucocorticoids, aromatase inhibitors, calcium and vitamin D supplementation). The case report included also detailed questions on the oral osteoporosis medication (dose, formulation, administration schedule, side effects, brand or generic). In all the patients bisphosphonate therapy had been prescribed in the instructions for use authorized for marketing in Italy. Moreover, the case report included questions related to concomitant disease and the Charlson Comorbidity Index was calculated [16]. Persistence was defined as the duration of time from initiation to discontinuation of therapy [8, 17]. The patients who discontinued bisphosphonate treatment for a duration longer than permissible gap (30 days) were considered to be non-persistent, even if bisphosphonates were subsequently restarted. Reasons for non-persistence with oral bisphosphonates were identified and classified as adverse events, costs, fear of adverse events, perceived absence of efficacy, other. The dates of the first prescription and the interruption of therapy were requested and confirmed with the clinical documentation. According to the WHO body mass index (BMI) categorization the subjects were classified in four groups: underweight (BMI ≤ 18.5 kg/m2), normal weight (BMI > 18.5 but ≤ 25 kg/m2), overweight (BMI > 25 kg/m2 but ≤ 30 kg/m2) and obese (BMI > 30 kg/m2). Physical activity was self-reported by the patients and recorded by the sum of work, home, and leisure activities for the last 12 months, graded from 1 (inactive) to 3 (very active).

Statistical analysis

The quantitative variables normally distributed were reported as mean ± standard deviation, while those not normally distributed reported as median and interquartile.

The association between different demographic, lifestyle and clinical characteristics and the outcomes were presented in the contingency table and statistically assessed using Chi-square test. The absence of multicollinearity was verified and the Hosmer–Lemeshow test was used to confirm the goodness-of-fit of the models to the data (p < 0.05). Univariate and multivariable logistic models were used to determine the independent factors associated to the persistence to a treatment with oral bisphosphonates. All Analyses were carried out by SPSS version 16.0.1 for Window.

Results

Of the 723 enrolled osteoporotic patients 58 were eliminated as a consequence of stringent inclusion/exclusion criteria (n = 39) and the lack of anthropometric or clinical data (n = 19). Therefore, the statistical analysis was carried out on a total of 665 osteoporotic patients (22 males and 643 females) with a mean age of 68.0 ± 9.0 years. In women the age of menopause was 48.4 ± 5.1 years and menopause was found to be spontaneous in 84.7% and surgical in the remaining 15.3%. Over half of the patients took alendronate weekly (n = 380; 57.1%), fewer patients took ibandronate monthly (n = 68; 10.2%) or risedronate (n = 212; 31.9%), while only 5 (0.8%) patients took clodronate (one capsule 400 mg daily).

Regarding oral bisphosphonate therapy, we evaluated whether the branded or generic drug was taken and it was found that 84.1% of subjects took a branded bisphosphonate, while the remaining 15.9% took the generic drug. The majority of patients were treated with a weekly formulation (75.0%), while the monthly formulation was taken by approximately ¼ of the patients (24.2%) and only a small minority took the daily formulation (0.8%). Bisphosphonates were taken as tablets by 75.4% of the study population, while 74 patients (11.1%) took bisphosphonates in the form of effervescent tablets and 90 patients (13.5%) as oral solution.

One hundred and ninety-one patients turned out to have stopped treatment (28.7%). Concerning the more common causes for the interruption of oral bisphosphonates we found that in about half of the patients, the interruption of therapy was due to adverse events (43.9%); two other important causes for discontinuation of therapy were fear of adverse events (23.3%) and perceived absence of efficacy of the treatment (15.8%). The cost of the drug, on the other hand, was found to affect persistence in 14 patients only (2.1%) (Fig. 1).
Fig. 1

Reasons for discontinuation of oral bisphosphonates treatments in 191 osteoporotic outpatients

The demographic and clinical characteristics of osteoporotic men and women, categorized by their persistence in continuing oral bisphosphonate therapy, are reported in Table 1. No differences were observed between the two groups for demographic parameters, physical activity, smoking attitude, familiar history of osteoporosis and fragility fractures.
Table 1

Demographic, lifestyles and clinical characteristics of 665 osteoporotic outpatients by discontinuation oral bisphosphonates therapy

Characteristics

Persisted with therapy (n = 474)

Discontinued therapy (n = 191)

p

Age (years)

68.2 + 9.0

67.7 + 9.0

0.09

Weight (kg)

62.9 + 10.9

61.7 + 13.1

0.12

Height (cm)

158.7 + 7.1

158.4 ± 6.4

0.8

BMI (kg/m2)

24.9 + 4.0

24.5 + 4.5

0.15

Smokinga

81/474 (17.1%)

42/191 (22.0%)

0.22

History osteoporotic fracturesa

232/474 (48.9%)

111/191 (58.1%)

0.23

Family history of osteoporosisa

168/474 (35.4%)

67/191 (35.19%)

0.95

GCS therapya

46/474 (9.7%)

16/191 (8.4%)

0.62

Alstherapya

43/474 (9.0%)

8/191 (4.1%)

< 0.05

Charlson Comorbidity Index (CCI)

4.24 + 1.58

4.25 + 1.55

0.16

Antioste oporotic treatmenta

 Daily

2/474 (0.4%)

3/191 (1.6%)

0.12

 Weekly

352/474 (74.3%)

147/191 (77.0%)

0.78

 Monthly

120/474 (25.3%)

41/191 (21.4%)

0.40

Therapy typea

 Branded

415/474 (87.6%)

144/191 (75.4%)

0.24

 Generic

59/474 (12.4%)

47/191 (24.6%)

<0.001

Bisphosphonates formulationa

 Tablets

344/474 (72.6%)

157/191 (82.2%)

0.33

 Soluble

130/474 (27.4%)

34/191 (17.8%)

<0.05

Calcium/Vitamin D Supplementsa

437/474 (92.2%)

175/191 (91.6%)

0.96

p values ≤ 0.05 were considered statistically significant

aCategorial variable (Chi-squared test, two sided)

In addition, the proportion of patients with a history of previous fractures was similar in both “persistent” and “discontinued” groups (48.9% and 58.1%, respectively). Instead, the prescription of the generic drug was significantly more frequent in the patients who stopped the treatment with respect to those who were persistent (24.6% vs 12.2%, respectively). No significant differences were observed between the two groups with regard to the number and severity of comorbidities and the use of glucocorticoids. Instead, the percentage of women treated with aromatase inhibitors was significantly higher (p < 0.05) among the patients who were persistent.

Figure 2 shows that the percentage of patients taking bisphosphonates in the form of effervescent tablets or oral solution was significantly higher (p < 0.05) in the “persistent” group than in the patients who discontinued therapy.
Fig. 2

Osteoporotic patients who interrupted or continued the treatment with oral bisphosphonates by different formulations

Table 2 shows the results of the univarite logistic regression analysis. The age over 70 years, the formulation and the form of bisphosphonates and the use of AIs were all associated with the discontinuation of treatment.
Table 2

Univariate logistic regression model to predict the discontinuation of the therapy with oral bisphophonates

Covariates

F

p value

Age > 70 years

3.741

0.053

History of osteoporostic fractures

1.275

0.259

GCS therapy

0.467

0.494

Alstherapy (no)

3.781

0.049

Charlson Comorbidity Index > 4

0.640

0.424

Bisphosphonate formulation (tablets)

5.402

0.034

Therapy type (generic)

11.308

0.001

The osteoporotic patients taking bisphosphonates in a soluble formulation was less likely to have low persistence to oral bisphosphonates (Table 3, Model 1). However, this association was no longer significant when the pharmaceutical formulation (generic vs branded) was included into the model; whereas the generic formulation and the age over 70 years were significantly associated to a premature discontinuation (Table 3, Model 2).
Table 3

Multivariate logistic regression model to predict the “discontinuation of the therapy with oral bisphophonates”

Covariates

Discontinuation of the therapy

p value

Odds ratio

95% confidence interval

Model 1

 Tabletsa

1.619

1.026–2.557

0.039

Model 2

 Age > 70 yearsb

1.486

1.029–2.146

0.034

 Genericc

2.265

1.419–3.616

0.001

Whole set of variables included into the Model 1: age > 70 years, history of osteoporostic fractures, GCS therapy, Als therapy, Charlson Comorbidity Index (CCI), bisphosphonates formulation. Whole set of variables included into the Model 2: age > 70 years, history of osteoporostic fractures, GCS therapy, Als therapy, Charlson Comorbidity Index (CCI), bisphosphonates formulation, therapy type

aDicothomous variables (ref. soluble)

b(Ref. age < 70 years)

cDicothomous variables (ref. branded)

Discussion

This study, carried out on a large cohort of elderly osteoporotic patients, analyzed the major factors that influence the persistence of anti-osteoporotic treatments with oral bisphosphonates in Italy. In the management of osteoporotic patients persistence is a crucial matter, given that higher persistence rates have been associated with further reductions in hip and overall fracture risk with a consequent reduction in costs [8, 9, 10].

In our study, we observed a persistence of about 70% and, therefore, slightly better with respect to that reported by other studies, and this may be explained by the fact that most of our patients were in therapy for just over 6 months. In fact, it is known that persistence decreases progressively with the prolongation of bisphosphonate therapy, presenting a sharp reduction between the first and second year of treatment [17, 18].

The most relevant findings of this retrospective study is represented by the fact that either the formulation or the generic/branded form of oral bisphosphonates play an important role in the persistence of treatment. In recent years, the use of generic formulations of bisphosphonates is greatly increased with respect to that of original brand. Several studies reported that generic forms of alendronate presented lower persistence rates as compared to branded alendronate due to an increase in upper gastrointestinal adverse events [19, 20]. Differences in excipients may be an important factor in the frequently reported differences in disintegration time between generic and brand bisphosphonates. Most commonly, generic versions of both alendronate and residronate disintegrate far more rapidly than branded drugs, increasing the potential for adverse events [7, 19, 20, 21]. The rapid disintegration onset times of generic bisphosphonates may be important as this could increase the possibility of drug exposure in both the mouth and the esophagus during swallowing, resulting in unwanted localized irritation. However, data directly evaluating the potential associations between different disintegration profiles and degree of gastric and esophageal irritation are scarce [22]. Nevertheless, other studies found no different persistence rate for branded or generic alendronate [17].

This study, in agreement with most literature, showed that the majority of patients who interrupt the therapy with bisphosphonates appear to do so because of drug-induced adverse events. Undoubtedly, among these adverse events, those affecting the upper gastrointestinal system are by far the most frequent [23]. Moreover, Goldshtein et al. [14] found that the most common reason cited for discontinuation of oral bisphosphonates was due to gastrointestinal side effects such as heartburn and gastric reflux. For this reason, recently, numerous efforts have been made by the pharmaceutical companies to develop alternative formulations to the classic oral administration of bisphosphonates, with the objective of decreasing gastrointestinal adverse events and consequently increasing compliance and pharmacological persistence especially in fragile patients [13].

In the present study, the use of the new formulations of bisphosphonate (effervescent tablets and drinkable solution) was found to be significantly associated with a lower risk of therapy interruption. The greatest persistence of these new alendronate formulations may probably be due to a lower incidence of gastro-intestinal side effects [23]. In particular, Hodges et al. [24] in a two-way cross-over study carried out in healthy women, found that the effervescent formulation was completely delivered to the stomach with no retention in the esophagus mucosa and was able to reduce stomach acidity so diminishing damage in cases of esophageal reflux. Coaccioli et al. [25], in a retrospective study carried out in 118 patients taking alendronate through a soluble solution at a weekly dose of 70 mg, found that after a 12 month treatment more than 90% of the patients remained persistent. Moreover, our study seems to suggest that the availability of drinkable formulation with a pleasant taste could play a positive role in improving persistence.

Another interesting finding of our study is represented by the fact that the women on treatment with aromatase inhibitors, as adjuvant hormone therapy for breast cancer, showed a fewer early interruptions of oral bisphosphonates therapy. This could be explained by the fact that these women better perceive the risk of suffering from osteoporotic fractures, that they connect directly to aromatase inhibitors and, therefore, perceive the need for a medication to prevent them. The crucial point is the need to better understand the process by which patients form intentions to take or not to take recommended medication. In fact, Shousboe [26] reported that the perceived necessity of medication would reflect not only the effectiveness of the medication but also that non-medicinal alternatives were not available. Moreover, perceived susceptibility to and perceived severity of fractures have been reported increase the perceived need of medications [26].

Several studies reported that weekly oral bisphosphonates may improve adherence with respect to the daily regimens [11]. In agreement with previous studies [17, 27] we found no difference between weekly and monthly regimens of oral bisphosphonates; this finding may suggest that the reduction of dosing frequency from weekly to monthly does not necessarily improve persistence.

Our study has some limitations. First, the retrospective nature of the study, prevents us from identifying further risk factors for poor persistence; second, the fact that all of the information was obtained from participants with no additional information from other sources, such as primary care physicians; third, the cost of medications and socio-economic status have not been taken into consideration, finally our study cannot assess the rate of discontinuation. Nevertheless, our study, carried out in a large and homogeneous sample size taken from osteoporotic elderly patients, provides us with a picture of the persistence with oral bisphosphonate in a context of real life clinical practice.

Conclusions

Poor persistence of drug treatment is the most important obstacle to overcome in the treatment of osteoporosis. The most common reason cited for discontinuation of oral bisphosphonates was due to gastrointestinal side effects. This study suggests that there may be differences in early interruptions between brand and generic formulations. The new drinkable formulations of bisphosphonate could be an interesting option able to reduce upper GI adverse events, thus increasing persistence and consequently anti-fracture efficacy.

Notes

Acknowledgements

We would like to thank Professor G. Cevenini for his advice in the revision of the statistical analysis.

Funding

No funding was received for this research.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, I declare no conflict of interest.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration. Procedures performed in this study did not involve animals.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    NIH consensus (2001) Development panel on osteoporosis prevention diagnosis and therapy. JAMA 285:785–795CrossRefGoogle Scholar
  2. 2.
    Hernlund E, Svedbom A, Ivergård M et al (2013) Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 8:136CrossRefGoogle Scholar
  3. 3.
    Kanis JA, McCloskey EV, Johansson H (2013) Scientific advisory board of the european society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO) and the committee of Scientific advisors of the international osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 24:23–57CrossRefGoogle Scholar
  4. 4.
    Hiligsmann M, Salas M, Hughes DA et al (2013) Interventions to improve osteoporosis medication adherence and persistence: a systematic review and literature appraisal by the ISPOR Medication Adherence and Persistence Special Interest Group. Osteoporos Int 24:2907–2918CrossRefGoogle Scholar
  5. 5.
    Kothawala P, Badamgarav E, Ryu S et al (2007) Systematic review and meta-analysis of real-world adherence to drug therapy for osteoporosis. Mayo Clin Proc 82:1493–1501CrossRefGoogle Scholar
  6. 6.
    Diaz-Perez A, Naylor KE (2017) Adherence working group of the international osteoporosis foundation and the European calcified tissue society. International osteoporosis foundation and European calcified tissue society working group. Recommendations for the screening of adherence to oral bisphosphonates. Osteoporos Int 28:767–774CrossRefGoogle Scholar
  7. 7.
    Kanis JA, Reginster JY, Kaufman JM et al (2012) A reappraisal of generic bisphosphonates in osteoporosis. Osteoporos Int 23:213–221CrossRefGoogle Scholar
  8. 8.
    Siris ES, Selby PL, Saag KG et al (2009) Impact of osteoporosis treatment adherence on fracture rates in North America and Europe. Am J Med 122:S3–13CrossRefGoogle Scholar
  9. 9.
    Patrick AR, Brookhart MA, Losina E et al (2010) The complex relation between bisphosphonate adherence and fracture reduction. J Clin Endocrinol Metab 95:3251–3259CrossRefGoogle Scholar
  10. 10.
    Rabenda V, Mertens R, Fabri V et al (2008) Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women. OsteoporosInt 19:811–818CrossRefGoogle Scholar
  11. 11.
    Bianchi ML, Duca P, Vai S et al (2015) Improving adherence to and persistence with oral therapy of osteoporosis. Osteoporos Int 26:1629–1638CrossRefGoogle Scholar
  12. 12.
    Gonnelli S, Caffarelli C, Rossi S et al (2016) How the knowledge of fracture risk might influence adherence to oral therapy of osteoporosis in Italy: the ADEOST study. Aging Clin Exp Res 28:459–468CrossRefGoogle Scholar
  13. 13.
    Brandi ML, Black D (2013) A drinkable formulation of alendronate: potential to increase compliance and decrease upper GI irritation. Clin Cases Miner Bone Metab 10:187–190PubMedGoogle Scholar
  14. 14.
    Goldshtein I, Rouach V, Shamir-Stein N et al (2016) Role of side effects, physician involvement, and patient perception in non-adherence with oral bisphosphonates. Adv Ther 33:1374–1384CrossRefGoogle Scholar
  15. 15.
    Modi A, Sajjan S, Michael Lewiecki E et al (2016) Relationship between gastrointestinal events and compliance with osteoporosis therapy: an administrative claims analysis of the US managed care population. Clin Ther 38:1074–1080CrossRefGoogle Scholar
  16. 16.
    Charlson ME, Pompei P, Ales KL et al (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383CrossRefGoogle Scholar
  17. 17.
    van Boven JF, de Boer PT, Postma MJ et al (2013) Persistence with osteoporosis medication among newly-treated osteoporotic patients. J Bone Miner Metab 31:562–570CrossRefGoogle Scholar
  18. 18.
    Reyes C, Tebe C, Martinez-Laguna D et al (2017) One and two-year persistence with different anti-osteoporosis medications: a retrospective cohort study. Osteoporos Int 28:2997–3004CrossRefGoogle Scholar
  19. 19.
    Ström O, Landfeldt E (2012) The association between automatic generic substitution and treatment persistence with oral bisphosphonates. Osteoporos Int 23:2201–2209CrossRefGoogle Scholar
  20. 20.
    Brown JP, Davison KS, Olszynski WP et al (2013) A critical review of brand and generic alendronate for the treatment of osteoporosis. Springer Plus 2:550CrossRefGoogle Scholar
  21. 21.
    Walker AD, Adachi JD (2011) In vitro disintegration studies of weekly generic and branded risedronate sodium formulations available in Canada. Curr Med Res Opin 27:1749–1754CrossRefGoogle Scholar
  22. 22.
    Grima DT, Papaioannou A, Airia P et al (2010) Adverse events, bone mineral density and discontinuation associated with generic alendronate among postmenopausal women previously tolerant to brand alendronate: a retrospective cohort study. BMC Muscoloskeletal Disorders 11:68–76CrossRefGoogle Scholar
  23. 23.
    Invernizzi M, Cisari C, Carda S (2015) The potential impact of new effervescent alendronate formulation on compliance and persistence in osteoporosis treatment. Aging Clin Exp Res 27:107–113CrossRefGoogle Scholar
  24. 24.
    Hodges LA, Connolly SM, Winter J et al (2012) Modulation of gastric pH by a soluble effervescent formulation: a possible mean of improving gastric tolerability of alendronate. Int J Pharm 432:57–62CrossRefGoogle Scholar
  25. 25.
    Coaccioli S, Celi G, Crapa ME et al (2014) Alendronate soluble solution: a higher adherence rate in the treatment of osteoporosis. Clin Cases Miner Bone Metab 11:123–125PubMedPubMedCentralGoogle Scholar
  26. 26.
    Schousboe JT (2013) Adherence with medications used to treat osteoporosis: behavioral insights. Curr Osteoporos Rep 11:21–29CrossRefGoogle Scholar
  27. 27.
    Netelenbos JC, Geusens PP, Ypma G et al (2011) Adherence and profile of non-persistence in patients treated for osteoporosis-a large-scale, long-term retrospective study in The Netherlands. Osteoporos Int 22:1537–1546CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Stefano Gonnelli
    • 1
    Email author
  • Carla Caffarelli
    • 1
  • Giulia Letizia Mauro
    • 2
  • Ombretta Di Munno
    • 3
  • Nazzarena Malavolta
    • 4
  • Silvia Migliaccio
    • 5
  • Ranuccio Nuti
    • 1
  1. 1.Department of Medicine, Surgery and NeuroscienceUniversity of Siena, Policlinico Le ScotteSienaItaly
  2. 2.Department of Surgical and Oncology SciencesUniversity of PalermoPalermoItaly
  3. 3.Rheumatology Unit, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  4. 4.Rheumatology UnitS.Orsola-Malpighi Teaching HospitalBolognaItaly
  5. 5.Department of Movement, Human and Health Sciences, Section of Health SciencesUniversity of Rome, Foro ItalicoRomeItaly

Personalised recommendations