Zuidgeest Marloes
email: marloeszuidgeestm.zuidgeest@nivel.nl

Sixma Herman

Rademakers Jany

Zuidgeest Msc
email: m.zuidgeest@nivel.nl

PhD H J Herman Sixma

J D J M Jany

Rademakers Phd

Linking powered by eXtyles Measuring patients' experiences with rheumatic care: the Consumer Quality Index Rheumatoid Arthritis

Keywords: consumer, experiences, rheumatoid arthritis, quality of healthcare

Objectives. Rheumatologists and other caregivers can learn from patients" experiences with the quality of care that can measured with the CQ-index Rheumatoid Arthritis (CQ-index RA) survey.

Methods. Patients with RA(n=590) received this survey were they rated their actual experiences and what they find important in rheumatic healthcare. Descriptive analyses and psychometric methods were used to test the reliability.

Results. The response rate was 69%. The items in the pilot instrument could be grouped into ten scales (α ranged from 0.77 to 0.94). The most important quality aspects according to patients concerned the alertness when prescribing medication. Providing patients with information on a special website of the hospital about RA was the highest quality improvement aspect.

Conclusion.

The results of this study show that the CQ-index RA is a reliable instrument for quality assessment from the patients" perspective. The instrument provides rheumatologists and other caregivers with feedback for service improvement initiatives.

INTRODUCTION

Quality of care has become increasingly important in the evaluation of healthcare and healthcare services [START_REF] Avis | Satisfying solutions? A review of some unresolved issues in the measurement of patient satisfaction[END_REF](2)[START_REF] Richards | Patients' priorities[END_REF]]. Evaluating rheumatic healthcare quality is a major issue given the care need profile of patients with rheumatoid arthritis(RA) and their long-term dependency on healthcare [START_REF] Jacobi | Health care utilization among rheumatoid arthritis patients referred to a rheumatology center: unequal needs, unequal care?[END_REF]]. Evaluation of quality of care is often performed by healthcare professionals.

However, patients" perspectives on healthcare quality differ from the views of healthcare professionals and policy makers [START_REF] Batalden | Quality in medicine--the view from the Hospital Corporation of America. An interview with Paul Batalden, M.D., HCA vice president for medical care (by Richard L. Reece)[END_REF][START_REF] Bensing | Doctor-patient communication and the quality of care[END_REF][START_REF] Potts | Views of patients and providers regarding the importance of various aspects of an arthritis treatment program[END_REF]. Also, patients" perspectives on the quality of care have become more prominent in research and policy since the introduction of the concept of patient-centered care in many countries (8;9). This concept aims to empower patients with respect to their healthcare decisions and to (re)structure the healthcare system according to their needs.

Patients" views on quality of care have often been conceptualised as patient satisfaction [START_REF] Kirsner | Patient satisfaction. Quality of care from the patients' perspective[END_REF][START_REF] Sitzia | Patient satisfaction: a review of issues and concepts[END_REF][START_REF] Van Campen | Quality of care and patient satisfaction: a review of measuring instruments[END_REF]. A disadvantage of these surveys is that the scores are extremely subjective, highly skewed(>90% are satisfied), and influenced by personal preference and patient expectation [START_REF] Yang | Patient's experience and satisfaction survey on general pratice: international development and Australian experience[END_REF]. Caregivers and healthcare services can not influence patients expectations, but can change the actual experiences. Therefore, a more refined and less subjective instrument for evaluating healthcare quality from the patients" perspective seems necessary. The Consumer Quality index (CQ-index) provides such an instrument (14;15). The CQ-index is based on two families of surveys that measures patients" experiences.

The first family of surveys that is used is the Consumer Assessment of Healthcare Providers and Systems (CAHPS ® ), which is well-established and widely used in the USA (www.cahps.ahrq.gov). This methodology comprises standardized protocols and manuals concerning sampling, data collection, data-entry, data-analysis and data reporting, which are also used as reference for CQ-index research. Furthermore, the lay-out and answering categories on a four-point scale (never, sometimes, usually, always), three-point scale (not a problem, a small problem, a big problem), global ratings (ranging from 0 to 10, with a score of 10 indicating the best possible score) and referring to the frequency of experienced events in a certain time period ("In the last 12 months, how often…") were taken from the CAHPS.

The second family of instruments that is used is QUOTE (QUality Of care Through the patient"s Eyes), which has been developed in the Netherlands [START_REF] Nijkamp | Quality of care from the perspective of the cataract patient. QUOTE cataract questionnaire[END_REF][START_REF] Sixma | Quality of care from the patients' perspective: From theoretical concept to a new measuring instrument[END_REF][START_REF] Sixma | Quality of care from the perspective of elderly people: the QUOTE-elderly instrument[END_REF][START_REF] Van Der Eijk | Quality of health care in inflammatory bowel disease: development of a reliable questionnaire (QUOTE-IBD) and first results[END_REF][START_REF] Van Campen | Assessing patients' priorities and perceptions of the quality of health care: the development of the QUOTE-Rheumatic-Patients instrument[END_REF]. From this methodology the questions about importance (answering categories "not important", "fairly important", "important" and "extremely important") were added into the CQ-index methodology. Also, the concept to include disease-specific items of health care services is derived from the QUOTE instruments. The combination of these survey features has as outcome that every CQ-index exists of two parts: one about patients" experiences and one about the importance patients award to quality aspects.

Within rapid development of CQ-index instruments (up to 25), priority has been given to the development of a new instrument for patients with RA. The CQ-index RA is a disease specific survey, designed to assess patients" experiences and importance on quality aspects.

Patients with RA are "heavy healthcare users", most of them use two types of healthcare services besides the rheumatologist [START_REF] Jacobi | Health care utilization among rheumatoid arthritis patients referred to a rheumatology center: unequal needs, unequal care?[END_REF]. For patients to decide which specific provider to choose, consumer-information about the quality of care of these providers can be helpful.

Measuring patient experiences enables us to provide such information. In addition, the CQindex allows professionals to compare the quality of care they provide with colleagues in the same profession. This instrument may also be an important tool for healthcare providers to Linking powered by eXtyles monitor their quality of care. Finally, the CQ-index information identifies elements of care that, according to patients, are particularly eligible for improvement.

The aim of this article is to provide an instrument to measure patients" experiences about the health care. For this purpose, information on the content and psychometric characteristics of the developed CQ-index RA, as well as on the importance patients assign to the different quality aspects are presented.

PATIENTS AND METHODS

The creation of the CQ-index Rheumatoid Arthritis questionnaire. The survey was formed following the protocols of the CQ-index standard, which is based on the CAHPS and the QUOTE (15;22). A draft questionnaire was constructed using input from two focus group discussions with in total 22 patients with RA, existing questionnaires measuring patients" experiences with quality of rheumatic care (i.e. QUOTE-Rheumatic patients [START_REF] Van Campen | Assessing patients' priorities and perceptions of the quality of health care: the development of the QUOTE-Rheumatic-Patients instrument[END_REF]) and professional guidelines for RA (developed by the Dutch Institute for Healthcare Improvement (CBO)). The draft questionnaire was presented to an expert panel (health insurance companies, a patient organization, healthcare providers, patients with rheumatoid arthritis) to assemble comments and improve the instrument. Their comments were included in the second draft of the questionnaire, which was used, after cognitive testing, to test its psychometric properties. Linking powered by eXtyles CQ-index RA Experience. The pilot instrument consisted of two parts, the CQ-index RA Experience and the CQ-index RA Importance. The first part, the CQ-index RA Experience, contained fifteen items on person characteristics (e.g. age, education, patient's self-reported physical and psychological health), six global ratings (of caregiver during control of care, professional who gives medication, specialized nurse, therapist, medical specialist who performs the surgical procedure, rheumatic care in general), and 114 experience items regarding the actual experiences of patients with specific quality aspects of care. Other items were instruction items or items with answering categories other than the standard format. The items were divided in sixteen themes (see Table 1).

<INSERT TABLE 1>

The answering formats of the experience items were: 1) never, sometimes, usually, and always, 2) not a problem, a small problem, and a big problem, and 3) yes and no. The global ratings ranged from 0 to 10, with a score of 10 indicating the best possible score. If questions were not applicable an answering option was added. The grade of education was dived in "no education and secondary education" and "higher than secondary education". The self-reported physical and psychological health was assessed using a five-point scale: "excellent", "very good", "good", "fair" and "poor". The instrument instructed respondents to reflect on their experiences in the last twelve months.

CQ-index RA Importance. In the second part, the CQ-index RA Importance, 69 importance items were included, which were designed to assess the importance that patients attribute to Linking powered by eXtyles aspects of healthcare, using a four-point scale: "not important", "fairly important", "important" and "extremely important". The importance survey contained fewer items because quality aspects such as "to be taken seriously" applied to healthcare professionals in general rather than each healthcare professional of a particular discipline.

Subjects.

A total of 590 Patients with RA were selected from the files of four health insurance companies. Inclusion criteria were: (1) being older than 18 years of age; (2) having received rheumatic care in the last twelve months (based on declared costs); and (3) not being approached in the past for other CQ-index surveys. Selecting patients from the files of health insurance companies provided us with a random selection of the RA population, which was heterogeneous in treatments they received.

Data collection. This study was conducted in the Netherlands in the summer of 2007. All selected patients received a mailing from their health insurance company with the request to fill out the CQ-index RA Experience and CQ-index RA Importance. A "thank you" card was sent to all patients one week later. Non-respondents received a second survey and letter in the fifth week, and a reminder letter in the seventh week. The mailing packs with the questionnaires included a stamped addressed envelope [START_REF] Dillman | Mail and internet surveys the tailerd Design Method[END_REF].

Analyses.

Response. The response rate was calculated after excluding the patients who were not willing or able to participate, replied double, or responded negatively to the question whether they had received rheumatic care in the past 12 months. Furthermore, patients who stated that Linking powered by eXtyles they did not answer the questions themselves and who filled out less then half of the core items (items that should be answered by all respondents) were also excluded (22;25). Subjects. To determine whether the respondents and non-respondents differ they were compared on age (t-test) and sex (χ 2 -test).

Dimension structure. Conducting one explorative factor analysis with a direct oblimin rotation was not possible, because not all items applied to all patients. Therefore, several explorative factor analyses (EFA) with a direct oblimin rotation were conducted on groups of different items (themes) of the experience survey to examine the structure of the questionnaire and the relationship between items with similar answering categories. The factor analyses were accurate if the Kaiser-Meyer-Olkin Measure of Sampling Adequacy (KMO) was higher then 0.60. The number of factors per factor analyze was determined by Kaiser"s criterion (Eigenvalues >1.00). If the factor loading of an item exceeded the criterion of 0.40, the item was assigned to that particular factor. If an item loaded across multiple factors, it was assigned to the factor where it had the highest loading.

Reliability. The internal consistency reliability of the scales from the experience data was estimated using Cronbach"s alpha, where an alpha value of 0.70 or more was considered satisfactory [START_REF] Cronbach | Coefficient alpha and the internal structure of tests[END_REF]. Item-total correlations (ITC) were also calculated, to correct for item overlap and check for homogeneity of the simple-summated scales, which were created from items that loaded strongly on the factors(criterion >0.4 ITC) [START_REF] Streiner | Health measurement scales: a practical guide to their development and use[END_REF]. For one module (first visit rheumatologist) the reliability of a scale was calculated by the Kuder-Richardson Formula 20 (KR-20), which is the alternative method to assess the reliability for dichotome items (yes/no) [START_REF] Kuder | The theory of the estimation of test reliability[END_REF]. Linking powered by eXtyles Importance. The importance scores were calculated to determine the mean importance of each quality aspect (not important=1, important=2, fairly important=3, extremely important=4).

Quality improvement score. This score represents the proportion of respondents who had have a negative experience ("never/ sometimes", "no" or "a big problem") on a quality aspect multiplied by the importance score of the same quality aspect (range 1 "not important" to 4 "extremely important"). The quality improvement score is a score that gives healthcare providers information about which quality aspects are particularly eligible for improvement; the higher the score, the more potential there is for improvement.

Analyses were performed using SPSS 14.0®.

RESULTS

Response.

At the end of the data collection period, 472 patients returned the CQ-index RA Experience en 445 patients returned the CQ-index RA Importance. After exclusion, the experience data of 407 patients (69%) and the importance data of 385 patients (65%) were analyzed.

Subjects. The majority of the respondents were female (72,7%), and had an education on a secondary or lower level (50%). The self-reported physical health was moderate (47%) or good (41%), and the self-reported psychological health was mostly good (61%) followed by very good (12%) and excellent (12%). Respondents and non-respondents differed from each other concerning age (mean age was 62.9 versus 59.7 years; t =2.86; p=0.004), but not concerning gender (χ 2 =1.76; p=0.18).

Dimensional structure experience survey. Eight explorative factor analyses (EFA) were performed for different themes of the CQ-index RA Experience survey (themes 4-10, 13; see Table 1). For one explorative factor analysis (theme 13 "Financial compensation") the KMO value was not sufficient (KMO=0.50). The primary factor loadings based on the pattern matrix are presented in Table 2. In total, eleven factors were formed:

<INSERT TABLE 2>

Reliability. The fourth column (α1) of Table 2 shows the Cronbach"s alpha coefficients for the eleven formed factors which ranged from 0.00 to 0.94. Three factors had poor reliability resulting in Cronbach"s alpha coefficients of 0.00, 0.37, and 0.39. Removal of any of the items did not increase the alpha coefficient to the threshold of 0.70 (see column 5 of Table 2), and therefore, we were not able to create reliable scales with these items. One factor displayed a relatively low reliability (factor 6; α=0.67), after removing Q50 from this factor, Cronbach"s Linking powered by eXtyles alpha increased to 0.86. The internal consistency was tested for a thirteenth factor consisting of seven dichotomous items. In this factor Q17 had a low item-total-correlation (ITC), which showed that this question does not fit well in this factor. Excluding this item resulted in a KR-20 coefficient of 0.86, indicating a good reliability for factor 13 "conduct rheumatologist".

Regarding the other formed scales, (except for the scales with a poor reliability) the item-total correlation was adequate. In total, ten reliable scales ranging from 0.77 to 0.94 were constructed (factors 1-2, 4-7, 9-11, 13; see Table 2).

Importance scores. Table 3 presents the ten most important quality aspects mentioned by the respondents. Patients rate the item "caregivers consider other medication when prescribing drugs" as the most important quality aspect (importance score= 3.7). Information about the risks and the long-term consequences of a surgical procedure, the process of the surgical procedure and the rules for what (not) to do after a surgical procedure are important (3.5-3.6).

The rapid accessibility and availability of care (3.5-3.6) are also valued highly. Finally, caregivers have to take patients seriously (3.5) and patients need to discuss arrangements about what to do when RA deteriorates (3.5). Items that did not fit a scale were candidates to be removed from the questionnaire (reliability analysis). Other arguments for adjusting this instrument was based on the dimensional structure, importance scores, and comments of expert panel. For more details see rapport of [START_REF] Zuidgeest | Reumatoide Artritis: meetinstrumentontwikkeling: kwaliteit van reumazorg vanuit het perspectief van patienten met reumatoide artritis (CQ-index Rheumatoid Arthritis: measurement development. Quality of rheumatic care through the patients[END_REF] [START_REF] Zuidgeest | Reumatoide Artritis: meetinstrumentontwikkeling: kwaliteit van reumazorg vanuit het perspectief van patienten met reumatoide artritis (CQ-index Rheumatoid Arthritis: measurement development. Quality of rheumatic care through the patients[END_REF].

<INSERT TABLE 3>

Quality improvement score. In Table 4, ten quality aspects with improvement scores are presented. A score of 2.13 is the highest quality improvement score for the quality aspect "information on a website of the hospital about RA". "Information about reimbursements and contributions about support and devices" (Q=1.69) and "general practitioner asked about having rigid joints" (Q=1.61) were second and third in this overview. Other aspects concerned "reporting of a mistake" (Q=1.59), "more information about adjustments at home" (Q=1.51), "support concerning domestic activities" (Q=1.44) and "personal care" (Q=1.35), and "talking with caregivers if something went wrong" (Q=1.34).

<INSERT TABLE 4>

DISCUSSION

The aim of this study was to illustrate that patients" experiences can be reliably measured with the CQ-index and therefore data collected with this instrument can be an important source to evaluate quality of care. The content, the psychometric characteristics of the CQ-index instrument for patients with RA, and patients" views on the quality of rheumatic care were investigated. Our findings show that the multidisciplinary provides us information regarding experiences of patients with RA with several healthcare professionals (rheumatologist, specialized nurse, therapist, occupational physician, medical specialist, psychological caregiver). The final version of the questionnaire consists of ten scales with good reliability ranging from 0.77 to 0.94. Analysis revealed that the utmost important issue according to patients" was alertness when prescribing drugs. Providing information on a special website of Linking powered by eXtyles the hospital about RA was the quality aspect that needs the most consideration, as appeared from the quality improvement score.

Measuring patient"s experiences to evaluate quality of care is relatively new and goes beyond measuring patient satisfaction which is a multidimensional concept, influenced by personal preferences and patient expectations. By separating the dimensions "experience" and "importance" individual providers and healthcare organizations get a clearer view on the quality aspects that are susceptible for improvement; where the actual care does not meet the needs and expectations of patients. Patients" experiences are useful as an extra source for quality assessment, next to clinical indicators and methods. . The fact that this new instrument represents a multidisciplinary survey is a rather unique feature, as most research predominantly focuses on a particular discipline, e.g. rheumatology [START_REF] Ward | Rheumatology visit frequency and changes in functional disability and pain in patients with rheumatoid arthritis[END_REF]. Jacobi et al. was the first who discussed research of multidisciplinary healthcare utilization among patients with RA with different caregivers (general practitioner, medical specialists, allied healthcare, home care). They reported inadequate quality in the field of rheumatic expertise, particularly for general practitioners, physiotherapists, home nurses and home help, and in the field of information on medication and treatment for rheumatologists and general practitioners [START_REF] Jacobi | Quality of rheumatoid arthritis care: the patient's perspective[END_REF]. We were able to partly replicate this finding in our study. We also found inadequate quality on the aspect "giving information about home adjustments" and on aspects regarding information topics. In our study home nurses, and home help were not evaluated. Linking powered by eXtyles Our finding that alertness when prescribing drugs is the utmost important aspect according to patients is not very surprising, considering the average daily intake of two doses of drugs [START_REF] Blomqvist | Rheumatoid arthritis in Sweden. Drug prescriptions, costs, and adverse drug reactions[END_REF].

The ten displayed quality aspects differed little (importance score between 3.49 and 3.65), which showed that patients with RA regard these quality aspects in general as "important" to "extremely important". The aspect with the highest possibility for improvement was providing of information on a special website of the hospital. A study of Culver and Chadwick revealed that the Internet is a poor source of English information for patients with RA. Quality information was scarce and finding information was time-consuming [START_REF] Culver | Internet information on rheumatoid arthritis: an evaluation[END_REF]. Hospitals may anticipate on this by providing their own information about RA as service to their patients.

Though the CQ-index RA was a relatively long questionnaire, the response rate was 69%. This is consistent with other disease-specific surveys [START_REF] Nijkamp | Quality of care from the perspective of the cataract patient. QUOTE cataract questionnaire[END_REF]. The fact that three reminders were sent may have contributed to the relatively high response [START_REF] Dillman | Mail and internet surveys the tailored Design Method[END_REF]. It is known that elderly women are more likely to return the questionnaire than young men [START_REF] Delnoij | Made in the USA: The import of American Consumer Assessment of Health Plan Surveys (CAHPS) Linking powered by eXtyles into the Dutch social insurance system[END_REF]. In our study, we also found that older patients returned the questionnaire more often than younger patients, there was however no difference between male and female respondents. This could have had an effect on the results, because older people generally report more positive experiences than younger people (36;37). In other words, the experiences of patients could be biased in a positive direction.

CQ-index instruments are based on a multi-phase development process, starting with focus group discussions and ending with large quantitative testing. In this large quantitative testing relevant case mix adjusters are selected and used in the instruments developed so far [START_REF] Damman | Developing a case-mix adjustment strategy to report consumers' health care experiences[END_REF]. Linking powered by eXtyles Also other CQ-index instruments have revealed good ability to measure differences between healthcare providers, so called discriminative power (39;40). Information derived from CQindex instruments was successfully translated in public choice information on a special website (www.kiesbeter.nl).

Because the CQ-index method is standardized in measuring consumer experiences, a big advantage is that quality information can be compared between different settings and/ or different healthcare sectors. This contributes to the increasing transparency and performance providing of different healthcare providers. Providers can look to each others performance and adopt, where necessary, initiatives that have been used successfully in the past.

In conclusion, it is possible to reliably measure patients" experiences with the quality of rheumatic care. The CQ-index RA is able to identify those aspects of care that require extra consideration. In addition, the instrument can be used in further surveillance tools in evaluating performance of different healthcare providers. Therefore, in a next phase, the CQindex RA will be adjusted and tested on its ability to discriminate between healthcare providers on the constructed scales and quality aspects. With two items in one scale, Cronbach"s alpha of scale if item is deleted (α2) can not be calculated; 1 , KR-20 in stead of α; i bold typeface factor loading: item does not meet factor loading criterion of 0.4; ii bold typeface a2: Chronbach"s alpha improves when item is deleted; iii bold typeface ITC: item does not meet item total correlation criterion of 0.4.

  (1) Conduct caregiver during control of care, (2) Competence caregiver during control of care, (3) Remaining items control of care, (4) Competence caregiver medication, (5) Conduct specialized nurse, (6) Competence specialized nurse, (7) Conduct therapist, (8) Remaining items therapist, (9) Conduct psychological care, (10) Conduct occupational physician, (11) Cooperation, and (12) Remaining items cooperation. With the exception of question 35 (Q35, factor 1, α=0.38), all items used in the scales exhibited factor loadings exceeding 0.40. Q35 was removed from factor 1. All items which did not fit in a scale were reported separately (not presented in this article).

  40. Stubbe JH, Gelsema T, Delnoij DM (2007) The Consumer Quality Index Hip Knee Questionnaire measuring patients' experiences with quality of care after a total hip or knee arthroplasty. BMC Health Serv Res 7:60 Medline. doi:10.1186/1472-6963-7-60

Table 2 .

 2 Factor loadings of the items in the CQ-index Experience according to the 8 explorative factor analysis with oblim rotation (EFA1-EFA8). Factor loading, Cronbach"s alpha whole scale (α 1),

	Cronbach"s alpha of scale if item deleted (α 2), and the item total correlation correcting for overlap
	(ITC) are displayed.
	nr	Item description	Factor	α1	α2	ITC
			loading
	EFA 1 Factor 1: Conduct caregiver control of care		0.86
		(rheumatologist or specialized nurse)
	Q20.	Caregiver took me seriously	0.83		0.85	0.66
	Q21.	Caregiver spent enough time	0.82		0.83	0.72
	Q22.	Caregiver listened carefully	0.88		0.81	0.80
	Q23.	Caregiver took interest in you as a person	0.88		0.80	0.77
	Q24.	Caregiver took into account your personal situation	0.80		0.86	0.68
	Q35.	Caregiver was always the same person	0.38 i		-	-
	EFA 1 Factor 2: Competence caregiver control of care		0.85
	Q29	Caregiver explained research results clearly	0.42		0.82	0.63
	Q30.	Discussed whether the current treatment was best for you	0.68		0.81	0.71
	Q31.	Decisions about treatment were shared between you and	0.73		0.81	0.71
		caregiver	0.61		0.80	0.76
	Q32.	Caregiver took into account your wishes about treatment	0.86		0.86 ii	0.41
	Q33.	Rapid access to rheumatologist if complaints got worse	0.74		0.83	0.60
	Q34.	Opportunity to ask questions
	EFA 1 Factor 3: Remaining items control of care		0.00.
	Q25.	Seen within 15 minutes of your appointment	-0.60		n.c.	-0.00 iii
	Q36.	Caregiver referred you to other caregivers if you wanted	0.69		n.c.	-0.00
	EFA 2 Factor 4: Competence medication giver		0.77
	Q39.	Caregiver was aware of your personal situation	0.81		0.72	0.57
	Q40.	Caregiver considered other medication when prescribing drugs	0.86		0.64	0.65
	Q41.	Receiving adequate assistance with administering drugs
			0.82		0.70	0.59
	EFA 3 Factor 5: Conduct specialized nurse		0.89
	Q44.	Specialised nurse took you seriously	0.82		0.86	0.76
	Q45.	Specialised nurse spent enough time	0.87		0.85	0.82
	Q46.	Specialised nurse listened carefully	0.79		0.85	0.80
	Q47.	Specialised nurse showed personal interest	0.86		0.89	0.64
	Q48.	Specialised nurse explained information clearly	0.79		0.87	0.65
	Q49.	Opportunity to ask questions	0.70		0.87	0.67
	EFA 3 Factor 6: Competence specialized nurse		0.77
	Q50.	Specialised nurse referred you to other caregivers if you wanted	0.70		0.86	0.30
	Q51.	Specialised nurse gave advice, instructions and/or education	0.78		0.41	0.66
		about RA

Table 3

 3 The ten highest importance scores Question To what extent would you consider the following important: consider your other medication when prescribing drugs. …the specialist explains the risks of a surgical procedure. … you have a rapid accessibility to a rheumatologist after referral. …the general practitioner quickly provides referral to rheumatologist. … you are being informed about long-term consequences of a surgical procedure. …you are being rapidly sent to the rheumatologist if your complaints get worse. …a specialist explains the surgical procedure. …caregivers take you seriously. …the specialist provides rules for what (not) to do after a surgical procedure. …discuss arrangements regarding what to do when RA deteriorates, like in an acute attack.

	importance score

…caregivers

Table 4 .

 4 Top ten quality improvement scores (Q) with corresponding importance scores (I) and experience score, as proportion negative experience (E) are displayed.

	Nr.	Quality aspect

ACKNOWLEDGEMENTS

This study was supported by the Netherlands Organization for Health Research and Development (ZonMw) and Stichting Miletus (a concordance of Dutch health insurance companies). The authors would like to acknowledge the contribution of the expert panel that participated in our study: A. Hartveld (Rheumatism Patients League), C. van Weert, Msc. (Stichting Miletus, director), C. de Vries, MD (insurance company VGZ [UVIT]), G.A. Bouman, Msc. (Stichting Miletus), Gertjan Vos, H. Bruins-Slot, MD, PhD (health insurance company Delta Lloyd, J.J. van Croonenborg, Msc.(the Dutch Institute for Healthcare Improvement, CBO), I.J.M. Harms, MD (health insurance company Menzis, M. Scholte-Voshaar (Rheumatism Patients League), M.H. Hemrika, MD. (insurance company Agis, P. Kortenhoeven (Rheumatism Patients League, chair expert panel), R. Huisman-Hatzmann (hospital Diakonessenhuis Utrecht, specialised nurse) and T.L. Jansen, MD, PhD (Commissioner Quality, Netherlands Associate for Rheumatology, rheumatologist).


A Ferrante

A R Giardina

F Ciccia

G Parrinello

G Licata

G Avellone

E Giardina

R Impastato

Professor Giovanni Triolo
email: g.triolo@unipa.it

Cattedra

Long-term anti-tumor necrosis factor therapy reverses the progression of carotid intima-media thickness in female patients with active rheumatoid arthritis

INTRODUCTION

Patients with rheumatoid arthritis (RA) are at high risk of developing coronary heart disease (CHD). There is evidence of increased carotid intima-media thickness (IMT) in young long-term RA patients receiving standard methotrexate (MTX) therapy ( 1) and of high rates of myocardial infarction in women affected by RA in the absence of overt clinical atherosclerosis (2-4). The accelerated atherosclerosis found in these patients is not easily explained by traditional risk factors, suggesting that a systemic inflammatory response in RA may play a role in atherogenesis and/or in accentuating established atherosclerotic risk factors [START_REF] Van Doornum | Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis?[END_REF].

Clinical and experimental data support the hypothesis that an effective control of inflammation may be of benefit in reducing cardiovascular risk in patients with RA. Recent studies in fact demonstrate the occurrence of endothelial dysfunction even in young patients with RA and low grade of inflammation [START_REF] Hansel | Endothelial dysfunction in young patients patients with long-term rheumatoid arthritis and low disease activity[END_REF][START_REF] Vaudo | Endothelial dysfunction in young patients patients with long-term rheumatoid arthritis and low disease activity[END_REF][START_REF] Sattar | Explaining how high grade systemic inflammation accelerates vascular risk in rheumatoid arthritis[END_REF]. Anti-TNFalpha treatment is capable to transiently improve endothelial function in RA and to reduce aortic stiffness to a level comparable to that of healthy individuals (9-11), directly implicating TNF-α as an important mediator of endothelial dysfunction in RA.

Conflicting data probably due to selection of patients, and duration of treatment were published on the effect of anti TNF therapy in reducing the risk of cardiovascular disease in patients with RA [START_REF] Maki-Petaja | Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy[END_REF][START_REF] Van Doornum | Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis[END_REF][START_REF] Irace | Effect of anti TNFalpha therapy on arterial diameter and wall shear stress and HDL cholesterol[END_REF][START_REF] Van Halm | Diseasemodifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study[END_REF][START_REF] Gonzalez-Juanatey | Effect of anti-tumor necrosis factor a therapy on the progression of subclinical atherosclerosis in severe rheumatoid arthritis[END_REF].

Aim of this study was to assess the role of long term therapy with standard (methotrexate) or anti-TNF therapy on the intima-media thickness (IMT) in no-overt atherosclerotic women with active rheumatoid arthritis.

METHODS

Study populations and design

The study was approved by the institutional review board of our medical centre and written informed consent was obtained from subjects enrolled. One hundred-forty-four female patients with documented RA, diagnosed according to the American College of Rheumatology criteria for RA [START_REF] Arnett | The american Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis[END_REF], were consecutively selected from the outpatient programme of the Academic Rheumatology Unit of the Palermo University.

Patients had to be age > 18 years, be methotrexate (MTX) naïve and to have active disease with ESR > 28mm 1h and Disease Activity Score [DAS] > 2.4. Exclusion criteria included previous treatment with DMARDs other than antimalarials and evidence of atherosclerosis, cardiac disease, hypertension, diabetes mellitus assessed by history, physical examination and standard 12-lead ECG. Patients were compared with baseline and every 3 months for two consecutive years. Patient"s global assessment, physician"s global assessment, physical disability score and patient"s assessment of pain were also evaluated. Disease activity was calculated by a modified version of the disease activity score [START_REF] Prevoo | Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis[END_REF]. Functional capacity was measured by the Health Assessment Questionnaire (HAQ) [START_REF] Fries | Measurement of patients outcome in arthritis[END_REF].

Patients were initially assigned to receive MTX administered orally or by intramuscolar weekly injection with a dosage of 10-20 mg. All the patients received folate supplementation. After three months therapy, non responders received in addition TNF-alpha blocking agents. In the last group of patients 20 were treated with infliximab (3 mg/Kg at week 0, 2, 6 and then every 6-8 weeks), 15 with etanercept (25 mg twice weekly) and 5 with adalimumab (40 mg every other week) Assumption of low dose of steroids (prednisone ≤ 10 mg /die) was also permitted.

Carotid Ultrasonography

The study was performed using an Hewlett Logic 500 Pro series General Electric ultrasound imaging system with an 10 MHz electric linear transducer. All study partecipants underwent carotid ultrasonography, which was performed by the same experienced research sonographer. A single interpreter, who was blinded to the identity of the study partecipants, interpreted the results. Patients were studied in the supine position with slight hyperextension of the neck. Both extracranial carotid arterial systems were scanned in multiple planes using high resolution B-mode ultrasound. Plaque was defined either as a distinct protrusion of > 1.5 mm into the vessel lumen or as definite echogenicity with a posterior echogenic shadow. IMT was measured from end-diastolic (minimun dimension) M-mode images of the far wall of the distal common carotid artery (CCA). Mean values of right and left carotid IMT (ca-IMT) are presented. The reproducibility of the IMT measurements was evaluated in 10 subjects within ten days of the first examination. The correlation coefficient for IMT was 0.96.

Laboratory Assessment

Baseline laboratory assessment, included routine chemistries, serum rheumatoid factor and anti-cyclic citrullinated peptide level. Lipid profile and inflammation pointers (ESR, CRP and fibrinogen) determination were performed at baseline and then every 3 months for two years. The erythrocyte sedimentation rate (ESR) was measured using the Westergren technique, and the C-reactive protein (CRP) by nephelometry.

Total cholesterol, triglyceride, and high-density lipoprotein cholesterol levels were determined by the enzymatic method. Low-density lipoprotein (LDL) cholesterol levels were calculated by the formula of Friedewald and co-workers [START_REF] Friedwal | Estimation of the concentration of low density lipoprotein in plasma, without use of preparative ultracentrifuge[END_REF] which provides reliable values up to a TG concentration of 8.0 mmol/l.

Statistical analysis

The results were compared by the paired and unpaired Student"s t-test.

RESULTS

During the recruitment period 144 women affected by RA were enrolled. Clinical and laboratory characteristics of the study participants (RA patients and controls) are summarized in Table 1. There was no significant difference in these variables between RA patients and controls. Twenty-five patients were excluded from the study because of the absence of informed consent in 19, and the presence of carotid plaque in 6. At the beginning of observation ca-IMT was 0.68 ± 0.08 (SD) mm in control subjects and 0.73 ± 0.09 in patients with RA (p < ) (figure 1). All patients were initially treated with methotrexate and low dose steroids. After three months 79 (responders) continued methotrexate for all the period of observation (group A); 40 patients started an anti-TNF agents (group B, not reponders to MTX alone). No significant difference was present in the demographic, clinical, and laboratory data in the two groups at baseline (table 2). A significant reduction from baseline of all clinical (DAS44, HAQ) and laboratory (CRP, Fibrinogen) parameters was reached after two years in both groups of patients (table 3). An increase in HDL cholesterol was observed in anti-TNF treated patients (48.06 ± 7.8 vs 51.6 ± 7.6; p < 0.05) (table 3). Ca-IMT was 0.68 ± 0.08 (SD) mm in control subjects. A level > 0.76 (mean + 1 SD, 95 percentile) was considered abnormal. ca-IMT was 0.722 ± 0.099 in group A and 0.737 ± 0.104 mm in group B. Levels in both groups of patients were significantly higher than in controls (p<0.01) (fig. 1). Fourteen patients in group A and 15 in group B had abnormal levels. No significant variation of ca-IMT was observed after two years in MTX-treated patients (0.717 ± 0.091, NS) (fig. 2). On the other hand a significant decrease was observed in TNF-treated patients (0.625 ± 0.094, p<0.001) (fig. 3).

DISCUSSION

Considerable evidence indicates that patients with rheumatoid arthritis (RA) are at greater risk of developing subclinical atherosclerosis and subsequently coronary heart disease (2-5). Although mechanisms involved are not clear, endothelial dysfunction, mediated by systemic inflammation seems to play a major role. Recent studies using "direct" measures of vascular function, such as pulse-wave analysis and flow-mediated vasodilatation confirmed the occurrence of significant endothelial dysfunction in long-term RA patients that correlates with markers of systemic inflammation [START_REF] Van Doornum | Screening for atherosclerosis in patients with rheumatoid arthritis: comparison of two in vivo tests of vascular function[END_REF][START_REF] Mäki-Petäjä | Rheumatoid arthritis is associated with increased aortic pulse wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy[END_REF]. Moreover untreated patients with RA have a less favourable atherogenic index mainly characterised by a decreased total cholesterol and relatively lower highdensity lipoprotein cholesterol (HDLc) levels, suggesting a close relationship between inflammation and dyslipidaemia [START_REF] Park | Lipid profiles in untreated patients with rheumatoid arthritis[END_REF]. Endothelial cell activation has been hypothesized to link RA with an early initiation of atherosclerosis [START_REF] Sattar | Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis[END_REF]. TNF may mediate endothelial dysfunction both directly and indirectly [START_REF] Sattar | Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis[END_REF]. In addition TNF has been demonstrated to directly interfere with the metabolic pathways of triglycerides and cholesterol [START_REF] Grunfeld | Tumour necrosis factor, cytokines and the hyperlipidemia of infection[END_REF], and therefore the persistence of these modified lipids in the circulation may promote the development of atherosclerotic lesions. Anti-TNF therapy is expecting to reduce the risk of cardiovascular disease in RA.

Anti-TNF treatment is in fact able to transiently improve endothelial function in RA, to reduce aortic stiffness to a level comparable to that of healthy individuals (9-11), directly implicating this cytokine as a mediator of endothelial dysfunction in RA, and to induce a modest, but sustained, increase in serum HDL-C levels, which may have in turn a favourable effect in reducing the cardiovascular risk in these patients [START_REF] Spanakis | Modest but sustained increase of serum high density lipoprotein cholesterol levels in patients with inflammatory arthritides treated with infliximab[END_REF].

All together these data suggest that an effective control of inflammation may be of benefit in reducing cardiovascular risk in these patients. ca-IMT measurements are widely used in observational studies to evaluate determinants and consequences of atherosclerosis [START_REF] Geroulakos | The carotid intima-media thickness as a marker of the presence of severe symptomatic coronary artery disease[END_REF][START_REF] Tang | Baseline reproducibility of B-mode ultrasonic measurement of carotid artery intima-media thickness: the European Lacidipine Study on Atherosclerosis (ELSA)[END_REF][START_REF] Salonen | Ultrasound B-mode imaging in observational studies of atherosclerotic progression[END_REF][START_REF] Bots | Carotid intima-media thickness measurements in intervention studies[END_REF]. Several studies have shown that increased ca-IMT confers risk of future coronary heart disease and stroke. Therefore, it has been suggested that measurements of carotid IMT may be used to identify high-risk subjects [START_REF] Grobbee | Carotid artery intima-media thickness as an indicator of generalized atherosclerosis[END_REF]. ca-IMT measurements are currently used in randomized controlled trials as a surrogate end point for cardiovascular morbidity and mortality on the premise that change in c-IMT reflects change in risk of cardiovascular disease. The main advantage of using ca-IMT is the considerable reduction in sample size and possibly in duration of follow-up [START_REF] Bots | Carotid intima-media thickness measurements in intervention studies[END_REF]. Data from 13 published RCTs that use ca-IMT progression as an outcome showed that overall weighed rate of change in mean common ca-IMT was 0.0147 mm/y (95% CI, 0.0122 to 0.0173), with a median SD of 0.053 [START_REF] Bots | Carotid intima-media thickness measurements in intervention studies[END_REF]. Recently has been demonstrated that the rate at which the IMT increased per unit of age steepened in proportion to the RA duration, from 0.154 mm/10 years among patients with RA for 7 years or less, to 0.295mm/10 years among patients with RA for 20 years or more [START_REF] Del Rincon | Acceleration of atherosclerosis during the course of rheumatoid arthritis[END_REF].

According to our knowledge this is the first prospective study that compare two long-term treatments that include methotrexate and TNF blocking agents, to evaluate the effect of therapy on the progression of subclinical atherosclerosis in patients with rheumatoid arthritis. Indeed more recently, Gonzalez-Juanatey and co-workers (15) demonstrated the progression of subclinical atherosclerosis in a very little series of patients with RA and severe disease, despite periodic treatment with infliximab. However, this observational study included a limited number of patients with a longer duration of disease (15.4 years in average) and a older age at study onset (> 50 years). To minimize the influence of confounding variables associated with increased IMT, such as age, sex and duration and severity of disease, we selected relatively homogeneous groups including only women with age <55 years without a history of atherosclerosis. Although significant improvements were seen in measures of disease activity, CRP and fibrinogen levels with both type of treatments, anti-TNF blocking agents but not methotrexate alone was capable to reduce IMT of carotid arteries of female RA patients in a two-year follow up.

In conclusion, our study indicates that anti-TNF blocking agents but not methotrexate is capable to reduce IMT of carotid arteries of females RA patients in a two years follow-up. This effect may be due to the blocking of a cytokine directly involved in the pathogenesis of atherosclerosis

Fig. 2

 2 Fig.2

Fig. 3 LinkingFigure 1 .Figure 2 .Figure 3 .

 3123 Fig.3

Table 1 .

 1 Characteristics of RA patients and healthy controls

	RA	Controls	P
	(N=144)	(N=78)

Table 2 .

 2 Characteristics of the two groups of patients

	Group B	Group A	P
	Anti-TNF-	MTX
	(N=40)	(N=79)

Table 3

 3 measures of activity and of lipid levels in the two groups of therapy

		Group A (Methotrexate)	Group B (anti-TNF)
	(mean ± SD)	Baseline	After 2 years	Baseline	After 2 years
	DAS	4.57 ± 1	2.39 ± 0,5*	4.62 ± 0.92	2.14 ± 0,32*
	CRP	4.54 ± 1.69	2.48 ± 1.12*	4.71 ±0.93	2.37 ± 0.79 *
	Fibrinogen	486 ± 85	353 ± 88*	487 ± 88	326 ± 78 *
	Cholesterol	203 ± 31.5	205 ± 30.7	206 ± 37.9	203.5 ± 36.46
	Triglicerid	109.7 ± 47.4	111.5 ± 39.9	106.7 ± 35.6	108.6 ± 30

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This work was supported in part by a grant from Ministero della Ricerca e della Università of Italy (MIUR).


Johann D Ringe¹

Gerd Möller

Prof. Dr. med Diederich Johann

Ringe
email: ringe@klinikum-lev.de

Differences in persistence, safety and efficacy of generic and original branded once weekly bisphosphonates in patients with postmenopausal osteoporosis -1-year results of a retrospective patient chart review analysis

Objective: To compare the changes on bone mineral density, the effects on persistence and adverse events, in patients treated for postmenopausal osteoporosis with either generic alendronate or with branded alendronate (Fosamax®) or branded risedronate (Actonel®) once weekly. Patients Linking powered by eXtyles 5

The importance of compliance, persistence and adherence for optimal therapeutic results

. Compliance differs from persistence, which is defined as the duration of time from initiation to discontinuation of therapy.

Persistence addresses how long a patient remains on therapy and it ends as soon as a patient stops taking a specified drug for a prolonged period of time. Adherence is the combination of compliance and persistence. Compliance, persistence and adherence are crucial to achieve also in patients real daily life situation the optimal therapeutic results demonstrated in clinical trials.

and methods: In this retrospective patient chart analysis we reviewed the one year observational treatment results of 186 women (ITT population) with postmenopausal osteoporosis. Patients from our out-patient department having started with once weekly bisphosphonate therapy between 36 to at least 12 months before this chart review were included in this comparative three arm study according to their treatment: A: Generic Alendonate 70 mg products, B: Branded Alendronate (Fosamax®) 70 mg once weekly and C: Branded Risedronate (Actonel®) 35 mg once weekly. All patients received basic therapy with 1200 mg calcium and 800 IU Vitamin D per day. Patient's bone mineral density (BMD) at lumbar spine and total hip was below -2.5 T-score, and they were with or without prevalent vertebral and non-vertebral fractures. Results: Data analysis of the 186 patient's shows an average increase in LS-BMD after 12 months of 2.8%, 5.2% and 4.8% for the groups A, B and C respectively. The respective mean changes at total hip were 1.5%, 2.9%, and 3.1%. At both sites, the mean increases in BMD were not different between the two groups receiving branded bisphosphonates (B, C) but for both were significantly higher than for the group treated with generic alendronate (A). At 12 months 68% of group A, 84% of group B and 94% of group C were still on bisphosphonate therapy. The persistence of patients treated with generic alendronate was significantly lower as compared to each of the two with branded bisphosphonates treated groups. The total number of patients reporting gastrointestinal adverse events were 32, 15 and 9 for group A, group B and group C respectively. Conclusions: Significantly lower increases of lumbar spine and total hip BMD with generic alendronate once weekly as compared to the two branded bisphosphonate originals (Fosamax®, Actonel®) were observed. The reasons for the 40-50% lower BMD increase rates when using the generic compounds are not know yet. At least in part the lower efficacy can be explained by a significantly lower degree of persistence with Linking powered by eXtyles 3 generic alendronate, which could be related to a higher incidence of gastrointestinal adverse events. Other reasons could be lower bioavailability or potency of generic alendronate.

Key words

Generic alendronate; branded bisphosphonates; risedronate; persistence; adverse events; efficacy.

Word count (excluding title, abstract, references, acknowledgements, and figure and table legends): 3757

Introduction

Osteoporosis is an important and very frequent chronic disease

Osteoporosis is a very common skeletal disease in aging populations and accordingly listed by the WHO and UNO among the 10 most important and most frequent chronic diseases of mankind [START_REF]DVO-Guideline for Prevention, Clinical Assesssment and Treatment of Osteoporosis for Women after Menopause, for Men after[END_REF][START_REF] Pfeilschifter | DVO-Guideline for prevention, diagnosis, and therapy of osteoporosis for women after menopause, for men after age 60. Executive summary guidelines[END_REF]. It is a progressive skeletal pathology characterised by loss of bone mass and quality and development of brittle bones that results in increased risk of fractures. The estimated worldwide number of new osteoporotic fractures for the year 2000 was 9.0 million, of which 1.6 million were at the hip, 1.7 million were at the distal forearm and 1.4 million were clinical vertebral fractures [START_REF] Johnell | An estimate of the worldwide prevalence and disability associated with osteoporotic fractures[END_REF]. Osteoporotic fractures have extensive clinical and economic consequences, and are a major public health concern. The important burden of osteoporotic fractures highlights the need for osteoporosis therapies with established high efficacy.

Bisphosphonates are the most common therapy for osteoporosis

Treatment options for osteoporosis have substantially improved in recent years [START_REF]DVO-Guideline for Prevention, Clinical Assesssment and Treatment of Osteoporosis for Women after Menopause, for Men after[END_REF][START_REF] Pfeilschifter | DVO-Guideline for prevention, diagnosis, and therapy of osteoporosis for women after menopause, for men after age 60. Executive summary guidelines[END_REF][START_REF] Desantis | Current and emerging therapies in osteoporosis[END_REF][START_REF] Kobayashi | Percutaneous vertebroplasty immediately relieves pain of osteoporotic vertebral compression fractures and prevents prolonged immobilization of patients[END_REF][START_REF] Theodorou | Treatment of osteoporosis: current status and recent advances[END_REF]: appropriate antiresorptive or anabolic medications are available to prevent future fractures.

Bisphosphonates inhibit osteoclast activity. Bisphosphonates are today's worldwide leading medication [START_REF] Liberman | Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group[END_REF][START_REF] Black | Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group[END_REF][START_REF] Cummings | Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial[END_REF][START_REF] Harris | Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group[END_REF][START_REF] Reginster | Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group[END_REF][START_REF] Ringe | Efficacy of risedronate in men with primary and secondary osteoporosis. Results of a 1-year study[END_REF][START_REF] Chesnut | Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis[END_REF][START_REF] Ringe | Intermittent intravenous ibandronate injections reduce vertebral fracture risk in corticosteroid-induced osteoporosis: results from a long-term comparative trial[END_REF][START_REF] Mcclung | Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group[END_REF][START_REF] Black | Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis[END_REF] and are recommended as first-line treatments for osteoporosis [START_REF]DVO-Guideline for Prevention, Clinical Assesssment and Treatment of Osteoporosis for Women after Menopause, for Men after[END_REF][START_REF] Pfeilschifter | DVO-Guideline for prevention, diagnosis, and therapy of osteoporosis for women after menopause, for men after age 60. Executive summary guidelines[END_REF]17,[START_REF]Nuova Nota 79 relativa all'osteoporosi[END_REF]. Two chemically distinct groups of bisphosphonates exist: Simple non-nitrogen-containing bisphosphonates (Non-N-BP's, e.g., Etidronate) and nitrogen-containing bisphosphonates (N-BP´s) e.g., Ibandronate, Alendronate, Zoledronate and Risedronate). There are two fundamentally, distinct components of the mechanism of action of nitrogen containing bisphosphonates (N-BPs) [START_REF] Ebetino | A computational model delineates differences in hydroxyapatite binding affinities of bisphosphonates in clinical use[END_REF][START_REF] Russell | Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy[END_REF]: These are 1) binding to the bone, and 2) binding to and inhibition of a key osteoclast enzyme farnesyl pyrophosphate synthase (FPPS). Regarding the oral bisphosphonates, only Risedronate and Alendronate have been proven to reduce vertebral and hip fracture risk in clinical trials [START_REF] Black | Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group[END_REF][START_REF] Cummings | Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial[END_REF][START_REF] Harris | Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group[END_REF][START_REF] Reginster | Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group[END_REF][START_REF] Ringe | Efficacy of risedronate in men with primary and secondary osteoporosis. Results of a 1-year study[END_REF][START_REF] Chesnut | Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis[END_REF][START_REF] Ringe | Intermittent intravenous ibandronate injections reduce vertebral fracture risk in corticosteroid-induced osteoporosis: results from a long-term comparative trial[END_REF][START_REF] Mcclung | Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group[END_REF][START_REF]Actonel ® 5 mg Filmtabletten Fachinformation[END_REF][START_REF] Roux | Efficacy of risedronate on clinical vertebral fractures within six months[END_REF][START_REF] Harrington | Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis[END_REF][START_REF] Silverman | Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: The risedronate and alendronate (REAL) cohort study[END_REF]. Zoledronate is an intravenous bisphosphonate therapy and has also been proven to reduce vertebral and hip fracture risk in clinical trials.

Introduction of generic bisphosphonates

During the last years an increasing number of generic alendronates were introduced based on bioequivalence data in numerous countries. Insurances and Health Care Providers increased pressure on physicians to prescribe mainly generic alendronate instead of branded original bisphosphonates like Fosamax® (Alendronate) and Actonel® (Risedronate). Little is known however about the provenience and quality of the still increasing number of generic Alendronates and clinical trials or observational postmarketing studies on bone mineral density and fracture efficacy, adverse events and compliance or persistence with these new "Alendronic acids" initiatives were never performed. This is an important gap of knowledge and means today physicians in many countries are supposed to prescribe mainly these cheaper generic Alendronates and at the same time they are unaware of the manufacturer of the respective compounds and whether efficacy and safety are really the same as were demonstrated for the original branded oral bisphosphonates in clinical or real practice studies. Also a higher rate of adverse events with generic Alendronates has often related from daily practice but only one study from Canada was published demonstrating indeed a higher incidence in gastro-intestinal side effects in patients treated with generic alendronate as compared to those treated with original once weekly bisphosphonates [START_REF] Papaioannou | Quantification and description of gastrointestinal adverse events (GI AES) in patients switched from branded Fosamax® to generic alendronate[END_REF]. Another major concern about these new "Alendronic acids" seems to be also a reduced medication compliance in clinical practice. An additional issue is related to the major disadvantage of the clinically utilized oral bisphosphonates which is their poor oral absorption from the gastrointestinal tract, typically less than 1% is absorbed. The poor absorption of bisphosphonates is most likely due to their very poor lipophilicity and charge, which prevents transcellular transport across the epithelial barriers. The question arises whether the absorption of generic Alendronates, and thus its bioavailability, is further altered because of the variation in galenic/tablet properties. This can potentially affecting the clinical outcome when used in the treatment of osteoporosis. The aim of this retrospective patient chart analysis study was to compare the effects on compliance, persistence, adverse events and on BMD in patients with postmenopausal osteoporosis treated with either different generic Alendronates once weekly or with the original branded compounds Fosamax® (Alendronate) or Actonel® (Risedronate) [START_REF]Actonel ® 5 mg Filmtabletten Fachinformation[END_REF][START_REF]Actonel ® einmal wöchentlich 35 mg Filmtabletten Fachinformation Januar[END_REF][START_REF]Fosamax ® 10 mg Fachinformation Fachinformation Februar[END_REF][START_REF]Fosamax ® einmal wöchentlich 70 mg Tabletten Fachinformation (Zusammenfassung der Merkmale des Arzneimittels, SPC) Mai[END_REF]. Relevant literature was reviewed.

Patients and study design

In this retrospective patient data analysis we reviewed clinical records of 204 women (50 years of age and older) with postmenopausal osteoporosis for relevant standard patient baseline data and for one year observational treatment results using a standardized patient chart data entry sheet. Patients were eligible from files of our out-patient department for this review if they were above 50 years of age and had initial BMD T-score values lower than -2.5 SD at lumbar spine (LS) and lower than -2.0 SD at the total hip (TH) with or without prevalent vertebral fractures. All participants gave verbal consent to participate in this retrospective patient data analysis. The study was approved by the local Hospital Research Ethics Committee. Selected patients were either without any pretreatment or with different previous treatments except bisphosphonates (e.g. HRT, raloxifen, tibolone, calcitonin, alfacalcidol, calcium, plain vitamin D). They had started with a once weekly bisphophonate therapy between three or at least one year before this evaluation and were allocated consecutively, according to their treatment to join one of three arms: (A) Generic alendonate 70 mg once a week, (B) Alendronate (Fosamax®) 70 mg once a week and (C) Risedronate (Actonel®) 35 Linking powered by eXtyles 7 mg once a week. A further selection criterion was initial prescription of 1200 mg calcium and 800 IU Vitamin D per day. BMD DXA-measurements (GE Lunar Prodigy™ DXA Bone Densitometer) and lateral vertebral morphometry (LVA, GE Lunar Prodigy™) or x-rays from thoracic and lumbar spine had to be performed at baseline and after 12 months. Patients of all three groups were excluded if they had been switched to another specific drug therapy (non-bisphosphonates) during the one year of follow-up. Switching to a generic or another branded original bisphosphonate in group B or C during the one year of observation was an exclusion criterion, while in group A switching from one to another generic alendronate was allowed. Not all information about the frequency of switching generic alendronates in group A and on the respective manufactures were available in the patient charts. In table 1 the initial characteristics of the 186 patients are given who fulfilled all above criteria. To assess patients persistence patients were asked using a standardized semi-structured questionnaire during the routine follow-up visit at month 12 how long they remained on therapy (calcium, vitamin D and/or and/or branded or generic bisphosphonate once a week) and when they stopped taking their osteoporosis drug (calcium, vitamin D and/or and/or branded or generic bisphosphonate once a week) for a prolonged period of time. Also during the routine follow-up visit at month 12 patients were asked how they take they drug regimen.

Compliance was determined asking the patient how they took their osteoporosis medication and if they took their it on time. Patient´s verbal feedback regarding compliance and persistence was rated and coded in the clinical record.

Statistical methods

186 of the 204 women with postmenopausal osteoporosis who fulfilled the inclusion criteria were included in the retrospective patient data analysis. Baseline characteristics were summarized using descriptive statistics. Formal statistical modeling was performed using SAS Version 9.1. All statistical tests were 2-sided at the 5% level of significance.

Results

Persistence

Table 2 shows the numbers and percentages of patients still on bisphosphonate therapy and on calcium/vitamin D supplementation after 12 months and the average months of intake for the three treatment groups. Still on their respective BP-therapies were 68% of group A (Generic Alendonate 70 mg products), 84% of B (Branded Alendronate (Fosamax®) 70 mg) and 94% of C (Branded Risedronate (Actonel®) 35 mg). The persistence of patients treated with Generic Alendonate 70 mg products was significantly lower as compared to each of the two original branded BP treated groups (Figure 1). In correspondence to these findings the persistence with calcium vitamin D supplementation was also lower in group A than in groups B and C.

Adverse events

During the 12 months of observation gastrointestinal adverse events were documented in 32 patients with Generic Alendonate 70 mg products therapy (group A), 15 with branded Alendronate 70 mg and 9 with branded Risedronate 35 mg once weekly (Table 3). The prevalence of gastrointestinal adverse events was significantly higher in Group A. Other non-gastrointestinal AEs were observed in 14 patients of group A and 9 and 5 resp. in groups B and C (Table 4). Only the difference between generic alendronates and branded Risedronate (Actonel®) 35 mg was statistically significant (Table 4).

Bone mineral density

The average increase in lumbar spine BMD after 12 months amounted to 2.8%, 5.2 and 4.8 for the groups A: Generic Alendonate 70 mg products, B: Branded Alendronate (Fosamax®) 70 mg and C: Branded Risedronate (Actonel®) 35 mg respectively (Figure 2). The respective mean changes at the total hip site were 1.5%, 2.9%, and 3.1%. At both sites the mean increases in BMD were not different between the two groups receiving original branded BP´s (B, C) but for both significantly higher than for group A treated with generic Alendonate 70 mg products (Figure 2).

Discussion

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The total number of patients reporting gastrointestinal events were significantly higher in patients treated with generic Alendonate 70 mg once weekly products then with the two branded original bisphosphonates treated patients. Data analysis shows after 12 months significantly higher average BMD increases at lumbar spine and at total hip for patients treated with the branded original bisphosphonates Alendronate (Fosamax®) 70 mg once weekly and Risedronate (Actonel®) 35 mg once weekly compared with generic Alendonate 70 mg once weekly products treated patients.

While a significantly higher incidence in gastro-intestinal adverse events with generic alendronates has been published [START_REF] Papaioannou | Quantification and description of gastrointestinal adverse events (GI AES) in patients switched from branded Fosamax® to generic alendronate[END_REF], this is the first report demonstrating a significantly lower increase of lumbar spine and total hip bone mineral density after one year with weekly 70 mg treatment with generic alendronate as compared to branded Alendronate (Fosamax®) or Risedronate (Actonel®).

As compared to generic Alendronate the average one year increase rates with original Alendronate (Fosamax®) or Risedronate (Actonel®) treatment at the lumbar spine were 86% and 71% higher respectively, and at the proximal femur 93% and 107% respectively (Figure 2). In our study the persistence of patients treated with generic Alendonate 70 mg once weekly products was significantly lower as compared to each of the two with branded original bisphosphonates treated patient groups.

What could be possible explanations for these significant differences in the therapeutic response?

1. Smaller increases in BMD due to lower persistence as a consequence of a higher rate of adverse events? 2. Lower bioavailability and higher rate of adverse events due to differences in disintegration and dissolution properties and esophageal transit time of tablets? 3. Smaller increases in BMD due a false intake of generic alendronate? 4. Smaller increases in BMD due to lower persistence as a consequence of additional psychological factors?

A combination of any of the previous 4 ones?

Smaller increases in BMD due to lower persistence as a consequence of a higher rate of adverse events Since a significantly lower persistence with generic bisphosphonates was shown in our study (Figure 1) this may be indeed the major factor leading to the highly significant lower increases in BMD at both measuring sites. Different studies in recent years proved significant correlations between compliance and therapeutic results during bisphosphonate therapy [START_REF] Caro | The impact of compliance with osteoporosis therapy on fracture rates in actual practice[END_REF][START_REF] Huybrechts | Assessment of compliance with osteoporosis treatment and its consequences in a managed care population[END_REF][START_REF] Weycker | Compliance with osteoporosis drug therapy and risk fracture[END_REF]. It was shown that noncompliance with antiresorptive therapies has been associated with a 16-50% increased risk of fracture [START_REF] Caro | The impact of compliance with osteoporosis therapy on fracture rates in actual practice[END_REF][START_REF] Huybrechts | Assessment of compliance with osteoporosis treatment and its consequences in a managed care population[END_REF][START_REF] Weycker | Compliance with osteoporosis drug therapy and risk fracture[END_REF][START_REF] Mccombs | Compliance with drug therapies for the treatment and prevention of osteoporosis[END_REF][START_REF] Siris | Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases[END_REF][START_REF] Penning-Van Beest | Loss of treatment benefit due to low compliance with bisphosphonate therapy[END_REF]. Also it was proven that subgroups with good compliance with bisphosphonates (e.g. over 80%) had higher increases in bone mineral density (BMD) and a significantly stronger effect on fracture risk than those with poor compliance [START_REF] Caro | The impact of compliance with osteoporosis therapy on fracture rates in actual practice[END_REF][START_REF] Sebaldt | Impact of non-compliance and non-persistence with daily bisphosphonates on longer-term effectiveness outcomes in patients with osteoporosis treated in tertiary specialist care[END_REF][START_REF] Siris | Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases[END_REF].

Lower bioavailability and higher rate of adverse events due to differences in disintegration and dissolution properties and esophageal transit time of tablets

The lower persistence in patients treated with Generic Alendronate 70 mg (and Generic Alendronate 70 mg) once weekly products which was shown in our study could be explained by the higher rates of gastrointestinal adverse events (Table 3). There exists some evidence that branded Risedronate might be a slightly better suitable alternative bisphosphonate drug for gastrointestinal sensitive patients compared to original branded or generic Alendronate [START_REF] Liberman | Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group[END_REF][START_REF] Black | Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group[END_REF][START_REF] Cummings | Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial[END_REF][START_REF]Fosamax ® 10 mg Fachinformation Fachinformation Februar[END_REF][START_REF]Fosamax ® einmal wöchentlich 70 mg Tabletten Fachinformation (Zusammenfassung der Merkmale des Arzneimittels, SPC) Mai[END_REF][START_REF] Taggart | Upper gastrointestinal tract safety of risedronate: a pooled analysis of 9 clinical trials[END_REF][START_REF] Mellström | Seven years of treatment with risedronate in women with postmenopausal osteoporosis[END_REF][START_REF] Adami | Upper gastrointestinal tract safety of daily oral risedronate in patients taking NSAIDs: a randomized, double-blind, placebo-controlled trial[END_REF][START_REF] Watts | Comparison of risedronate to alendronate and calcitonin for early reduction of nonvertebral fracture risk: results from a managed care administrative claims database[END_REF][START_REF] Lanza | Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women[END_REF][START_REF] Thomson | 14 day endoscopy study comparing risedronate and alendronate in postmenopausal women stratified by Helicobacter pylori status[END_REF][START_REF] Adachi | Tolerability of risedronate in postmenopausal women intolerant of alendronate[END_REF][START_REF] Degroen | Esophagitis associated with the use of alendronate[END_REF]. Two recent studies have shown differences in tablets properties that might explain different rates of adverse events. An in vitro study compared the disintegration and dissolution of once weekly original branded Risedronate (Actonel®) and original branded Alendronate (Fosamax®) tablets with 26 different Generic Alendronate copies from Canada, Germany, the Netherlands and UK [START_REF] Dansereau | In vitro disintegration and dissolution studies of once-weekly copies of alendronate sodium tablets (70mg) and in vivo implications[END_REF]. The mean disintegration times of the Generic Alendronate tablets in vitro ranged from 14 to 342 seconds (5.7 min) [START_REF] Dansereau | In vitro disintegration and dissolution studies of once-weekly copies of alendronate sodium tablets (70mg) and in vivo implications[END_REF]. The mean disintegration time of the branded product tablets (Actonel® and Fosamax®) ranged only from 43 to 78 seconds [START_REF] Dansereau | In vitro disintegration and dissolution studies of once-weekly copies of alendronate sodium tablets (70mg) and in vivo implications[END_REF]. Six of the 26 companies market alendronic acid tablets had very rapid disintegration times which are similar to those of orally disintegrating tablets (non-bisphosphonates) [START_REF] Dansereau | In vitro disintegration and dissolution studies of once-weekly copies of alendronate sodium tablets (70mg) and in vivo implications[END_REF]. Since there is no established disintegration time for Alendronate tablets there can be no assurance that the Generic Alendronate copy tablets are equivalent to the branded product in terms of esophageal drug exposure [START_REF] Dansereau | In vitro disintegration and dissolution studies of once-weekly copies of alendronate sodium tablets (70mg) and in vivo implications[END_REF].

Another trial evaluated and compared esophageal transit times and in vivo disintegration of one branded risedronate and two generic formulations of alendronic acid tablets [START_REF] Perkins | Esophageal transit and in vivo disintegration of branded risedronate sodium tablets and two generic formulations of alendronic acid tablets: A single-center, single blind, si-period crossover study in healthy female subjects[END_REF], that are commercially available in Canada and the United Kingdom. It was shown, that the two generic formulations of alendronic acid tablets had significant slower transit times than compared with the branded risedronate (Actonel®) tablet tested [START_REF] Perkins | Esophageal transit and in vivo disintegration of branded risedronate sodium tablets and two generic formulations of alendronic acid tablets: A single-center, single blind, si-period crossover study in healthy female subjects[END_REF]. The branded risedronate tablet had a significantly faster transit time than the two generic formulations of alendronate tested [START_REF] Perkins | Esophageal transit and in vivo disintegration of branded risedronate sodium tablets and two generic formulations of alendronic acid tablets: A single-center, single blind, si-period crossover study in healthy female subjects[END_REF]. This is of importance for patients because delayed esophageal transit or disintegration of oral bisphosphonate tablets before they enter the stomach could cause iatrogenic complications. Different formulations of generic bisphosphonate tablets meeting regulatory requirements may have substantial differences in pharmaceutical attributes from the branded product that may result in different characteristics during esophageal transit. A potential concern is that the pharmaceutical attributes of the various copy alendronate formulations may affect the potential for local irritation and tolerability, especially in the upper gastrointestinal tract. Epstein and colleagues [START_REF] Epstein | Disintegration and esophageal irritation profiles of alendronate formulations: Implications for clinical safety and efficacy[END_REF] showed a greater irritant response from a copy Alendronate tablet (Novo-Alendronate † 10 mg) in a rabbit injection study and in a dog esophageal study (Alendronate Sodium Tablets, Teva Industries, Petah-Tikva, Israel) compared to the branded innovator product (Alendronate sodium tablets, 10 mg). The differences were attributed to the pharmaceutical preparation, since the active ingredient (Alendronate sodium) and the dose were similar between the copy Alendronate tablets and the branded tablets. The same authors (50) also evaluated the disintegration and dissolution profiles of 13 copy Alendronate tablets available in Latin America.

From a safety perspective, the authors concluded that for the rapidly disintegrating formulations there is a chance that disintegration may occur in the mouth and/or the esophagus during swallowing of the tablet. This could increase the duration and extent of oral and esophageal tissue exposed to semi-particulate alendronate and thereby increase the risk of serious mucosal irritation and ulceration [START_REF] Epstein | Disintegration/dissolution profiles of copies of Fosamax (alendronate)[END_REF]. From an efficacy perspective, Epstein et al. also concluded that tablets that disintegrate faster than branded Alendronate sodium tablets (1.4 min) could result in reduced efficacy because the premature disintegration may be associated with semi-particulate Alendronate being retained within the esophagus, increasing the likelihood of contact with ingested food, saliva, mucus or liquids, thereby reducing the bioavailability or altering the pharmacokinetics. The bioavailability and therefore the efficacy of some generic Alendronate products due to very short disintegration times of the tablets (and a significant slower esophageal transit time of Generic Linking powered by eXtyles 12 Alendronate tablets) could be reduced. Generic Alendronate tablets with very short disintegration times start to disintegrate very quickly already in the mouth and esophagus. The already low intestinal absorption rates of these generic bisphosphonate drugs could be further decreased and full efficacy in terms of BMD increases not reached. The difference in the gastrointestinal safety and tolerability profile in favour for Risedronate vs Alendronate could together with the inferior disintegration and dissolution characteristics and significant slower esophageal transit time of once weekly generic Alendronate tablets explain the higher rates of gastrointestinal adverse events and lower efficacy detected in patients treated with Generic Alendronate in our study. Higher rates of gastrointestinal adverse events could have implications on persistence for patients which could lead to smaller increases in BMD. All together the described inferior gastrointestinal safety and tolerability profile of Alendronate compared to Risedronate would become even worse due to differences in disintegration and dissolution properties and a significant slower esophageal transit time of Generic Alendronate tablets. This could due to the higher rates of gastrointestinal adverse events (Table 3) and lower bioavailability have implications on persistence and on efficacy for patients which could lead to smaller increases in BMD.

Smaller increases in BMD due a false intake of generic Alendronate

A prerequisite of good therapeutic results in osteoporosis with the oral N-BP´s like Risedronate or Alendronate is the correct intake. Bioavailability of oral bisphosphonates is poor due to low intestinal absorption rates [START_REF] Lin | Bisphosphonates: A Review of their pharmacokinetic properties[END_REF]. The correct intake of a poorly absorbed bisphosphonate tablet is even more important if it is only given once per week. Food, calcium and other polyvalent cations can further decrease the absorption of these drugs, due to complex formation [START_REF] Fleisch | Bisphosphonates in Bone Disease: From the Laboratory to the Patient[END_REF]. To ensure unimpaired intestinal absorption, correct intake of the bisphosphonate on an empty stomach in upright position early in the morning with a glass of tap water and avoidance of any other beverage, food or medicines at least 1/2 an hour thereafter is required for Risedronate and Alendronate. Non-compliance with these instructions may lead to a lower absorption of the bisphosphonate with a risk of impaired treatment outcome. The risk of mistakes and reduced Linking powered by eXtyles 13 compliance when treating osteoporosis with a weekly oral bisphosphonate may be enlarged by frequent changes of prescribed or dispended bisphosphonates often without physicians not having the time to explain the reasons appropriately. Frequent changes of prescribed or dispended bisphosphonates especially generic Alendronate tablets and packages could lead to a complexity of therapy and a less good understanding of the regimen and thereby decrease the chance of a correct and effective medication. Therefore the likelihood to meet therapeutic goals of the therapy can be decreased.

Smaller increases in BMD due to lower persistence as a consequence of additional psychological factors

There could exist other additional factors that may explain differences in compliance and persistence and therefore efficacy. It cannot be excluded that besides adverse events psychological factors may contribute to a reduced persistence with generic alendronates. The knowledge about being treated with generics may have an influence on patients behaviour. The perception of receiving a cheap or "second choice" medication may considerably reduce the acceptance and compliance in individual patients. Also in the above cited Canadian study looking for gastrointestinal adverse events after switching from branded Alendronate to generic Alendronate there were significantly more adverse events during the second treatment phase although the patients were unaware of having been switched to generics [START_REF] Papaioannou | Quantification and description of gastrointestinal adverse events (GI AES) in patients switched from branded Fosamax® to generic alendronate[END_REF].

Study limitations

The present retrospective single centre-study under practical real life conditions has a few limitations mainly due to the way data have been collected. As with all observational studies, systematic errors (e.g. selection bias) may be the basis for the observed results [START_REF] Grimes | Bias and causal associations in observational research[END_REF]. On the other hand in our study there were no statistical differences in measurable patients characteristics between the 3 cohorts of patients at initiation of therapy. Strengths of this study include that all interviews regarding compliance and persistence were conducted by one interviewer using a standardized semi-structured questionnaire designed to analyze a clearly study outcome. However, this design has limitations. As a survey, it evaluates a patient's level of present understanding of the dosing instructions, compliance and persistence but cannot truly represent the respondent's previous behaviour in taking the medication. Given that the long-term treatment goal is to improve adherence with bisphosphonates, randomization of women to either branded or Generic bisphosphonates with assessment of adherence would be an improved design for future clinical prospective studies. The strength of observational studies can be the generalizability of results. In contrast, the generalizability of results from randomized trials to a real world setting can be limited by differences between the two in relation to expertise of health care provider, quality of medical care, course of therapy, and types of patients [START_REF] Black | Why we need observational studies to evaluate the effectiveness of health care[END_REF]. For example, it has been observed that the majority of patients considered candidates for osteoporosis therapy by their physician would not meet the eligibility criteria for inclusion in the randomized trials [START_REF] Dowd | Study subjects and ordinary patients[END_REF].

Summary and conclusions

Significantly lower increases of lumbar spine and total hip BMD with generic alendronate once weekly as compared to the two branded originals (Fosamax®, Actonel®) were observed. The reasons for the 40-50% lower BMD increase rates when using the generic compounds are not know yet. At least in part the lower efficacy can be explained by a significantly lower degree of persistence with generic alendronate, which could be related to a higher incidence of gastrointestinal adverse events. Other reasons could be lower bioavailability or potency of generic alendronate. We conclude from our study results that in daily practice there may be a high risk of a relatively reduced compliance with generic alendronate as compared to the original branded once weekly bisphosphonate tablets. This may considerably impair therapeutic outcomes and from a health economic point of view the lower price of generic alendronate will be no longer an advantage. Further studies to prove the possible risk of a reduced therapeutic effectiveness when prescribing generic alendronate are urgently needed.

Figure 1 :

 1 Figure 1: Persistence with bisphosphonate therapy and Calcium/Vitamin D supplementation (% patients at month 12).

Figure 2 :

 2 Figure 2: Mean percent changes in lumbar spine (LS) and total hip (TH) after 12 months.

Figures:Figure 1 :%Figure 2 :

 12 Figures:

Actonel®

  p<0.05, vs Actonel p<0.01, Fos.vs Act. ns

Fosamax®

  B ns, B vs C ns, A vs C p< 0.05

Table legends :Table 1 :

 legends1 Baseline characteristics of patients.

Table 2 :

 2 Persistence with bisphosphonate therapy and Calcium/Vitamin D supplementation at month 12.

Table 3 :

 3 Number of patients with gastrointestinal adverse events during the 12 months follow-up period.

Table 4 :

 4 Number of patients with non-gastrointestinal adverse events during the 12 months follow-

	up period.

Table 1 : Baseline characteristics of patients*

 1

			Gen. Aln.	Fosamax®	Actonel®
	Number of patients (n)	62	62	62
	Mean age (years)		63.7	64.2	65.8
	Mean height (cm)		165.5	164.0	162.5
	Mean weight (kg)		70.2	69.6	68.5
	LS-BMD (T-Score)		-3.05	-3.11	-3.16
	TH-BMD (T-Score)		-2.91	-2.81	-2.87
	Pat. with preval. (n)	35	38	41
	vert. fractures	(%)
			56%	61%	66%
	Pat. with preval. (n)	17	19	20
	non-vert-fractures (%)
			27%	31%	32%

*No signif. diff. between groups

Table 2 : Persistence with bisphosphonate therapy and calcium/vitamin D supplementation at month 12

 2

	Pat. still on BP	(n)	40	52	58
	at month 12 (%)		68%	84%	94%
	Mean duration of (m)	9.5	11.0	11.6
	intake of BP*
	Pat. still on Ca/D (n)	43	51	52
	at month 12 (%)		73%	82%	84%
	Mean duration of (m)	8.8	10.2	10.7
	Intake of Ca/D

*All patients (ITT-Population)

Table 4 : Number of patients with non-gastrointestinal adverse events* during the 12 months follow-up period

 4 Vert. and non-vert Fx were captured as AE (i.e. clinical Fx)

				Actonel®
				(n=62)
	Arthralgia	2	2	1
	Bone pain	1	1	0
	Muscle cramps	2	1	0
	Headache	2	0	1
	Dizziness	1	1	0
	Vertebral Fx	4	3	2
	Non-vert. Fx	2	1	1
	All other AE*	14	9	5

*

Acknowledgements:

This are results of an investigator initiated trial. Johann D. Ringe, MD, PhD was the principal investigator and he received no payments related to the collection and evaluation of patient's data and preparation of the manuscript from any pharmaceutical company. Johann D. Ringe, MD, PhD received consultancy fees and other payments from MSD Sharp & Dohme, Procter & Gamble Pharmaceuticals-Germany GmbH, Lilly Deutschland, Sanofi-Aventis Deutschland GmbH. Gerd Möller, MD, PhD, Health Economist (ebs) was an employee of Procter & Gamble Pharmaceuticals-Germany GmbH, D-65824 Schwalbach am Taunus, Germany from May 15th 2001 until September 5th 2008. Gerd Möller, MD, PhD, Health Economist (ebs) received no consultancy fees and other payments from any pharmaceutical company.