Rheumatol Int (2009) 30:213221

DOI 10.1007/s00296-009-0940-5

O R I G I N A L A R T I CL E

DiVerences in persistence, safety and eYcacy of generic

and original branded once weekly bisphosphonates
in patients with postmenopausal osteoporosis: 1-year results
of a retrospective patient chart review analysis
Johann D. Ringe Gerd Mller

Received: 24 February 2009 / Accepted: 23 April 2009 / Published online: 9 May 2009
Springer-Verlag 2009

Abstract The objective of this study was to compare the

changes on bone mineral density, and the eVects on persistence and adverse events in patients treated for postmenopausal osteoporosis with generic alendronate or with branded
alendronate (Fosamax) or branded risedronate (Actonel)
once weekly. In this retrospective patient chart analysis, we
reviewed the 1-year observational treatment results for 186
women (ITT population) with postmenopausal osteoporosis.
Patients from our outpatient department, who had started
with once-weekly bisphosphonate therapy between 36 and 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 1,200 mg calcium and 800 IU
vitamin D per day. Patients 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. Data analysis regarding the 186 patients 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 diVerent between
the two groups receiving branded bisphosphonates (B, C) but
for both were signiWcantly 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 signiWcantly lower as compared to
each of the two with branded bisphosphonate-treated groups.
The total numbers of patients reporting gastrointestinal
adverse events were 32, 15 and 9 for group A, group B, and
group C, respectively. SigniWcantly 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 4050% lower BMD increase rates when using the
generic compounds are not known yet. At least in part the
lower eYcacy can be explained by a signiWcantly 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.

J. D. Ringe
Medizinische Klink IV, Klinikum Leverkusen,
University of Cologne, 51375 Leverkusen, Germany

Keywords Generic alendronate Branded

bisphosphonates Risedronate Persistence
Adverse events EYcacy

G. Mller
Amgen (Europe) GmbH, Dammstrasse 23, P.O. Box 1557,
6301 Zug, Switzerland
e-mail: gmoeller@amgen.com
J. D. Ringe (&)
West German Osteoporosis Center (WOC) and Medizinische
Klinik IV, Klinikum Leverkusen Teaching Hospital
of the University of Cologne, 51375 Leverkusen, Germany
e-mail: ringe@klinikum-lev.de

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

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214

among the ten most important and most frequent chronic

diseases of mankind [1, 2]. It is a progressive skeletal
pathology characterized 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 [3]. 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 eYcacy.
Bisphosphonates are the most common therapy
for osteoporosis
Treatment options for osteoporosis have substantially
improved in recent years [1, 2, 46]: appropriate antiresorptive or anabolic medications are available to prevent future
fractures. Bisphosphonates inhibit osteoclast activity. Bisphosphonates are todays worldwide leading medication
[716] and are recommended as Wrst-line treatment for
osteoporosis [1, 2, 17, 18]. Two chemically distinct groups
of bisphosphonates exist: simple non-nitrogen-containing
bisphosphonates (Non-N-BPs, e.g., Etidronate) and nitrogen-containing bisphosphonates (N-BPs), e.g., Ibandronate, Alendronate, Zoledronate, and Risedronate. There are
two fundamentally distinct components of the mechanism
of action of nitrogen-containing bisphosphonates (N-BPs)
[19, 20]: 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 [8
15, 2124]. Zoledronate is an intravenous bisphosphonate
therapy and has also been proven to reduce vertebral and
hip fracture risk in clinical trials.
The importance of compliance, persistence and adherence
for optimal therapeutic results
The therapeutic aim of reducing the risk of fractures
requests a persistent intake of an eVective long-term medication [1, 2]. The eVectiveness of a treatment, however,
depends not only on the eYcacy of the used medication but
also on persistent drug intake of patients [2528]. Drugs do
not work in patients who do not take them. Compliance is
basically adherence to a drug regimen as in taking medications correctly and on time. It can be deWned as the extent
to which a patient acts in accordance with the prescribed
interval and dose of a dosing regimen. Compliance is usually measured over a period of time and reported as a

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Rheumatol Int (2009) 30:213221

percentage [29]. Compliance diVers from persistence,

which is deWned as the duration of time from initiation to
discontinuation of therapy. Persistence indicates how long a
patient remains on therapy and it ends as soon as a patient
stops taking a speciWed drug for a prolonged period of time.
Adherence is the combination of compliance and persistence. Compliance, persistence and adherence are also crucial to achieve the optimal therapeutic results in patients
real daily life situation as demonstrated in clinical trials.
Introduction of generic bisphosphonates
During the past 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
eYcacy, 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 eYcacy 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 eVects in
patients treated with generic alendronate as compared to
those treated with original once weekly bisphosphonates
[30]. Another major concern about these new Alendronic
acids seems to be also the 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 aVect the clinical outcome when used in the treatment
of osteoporosis. The aim of this retrospective patient chart
analysis study was to compare the eVects on compliance,
persistence, adverse events and on BMD in patients with

Rheumatol Int (2009) 30:213221

postmenopausal osteoporosis treated with diVerent generic

alendronates once weekly or with the original branded
compounds Fosamax (Alendronate) or Actonel (Risedronate) [21, 3133]. 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 1-year observational treatment results
using a standardized patient chart data entry sheet. Patients
were eligible for this review, from Wles of our out-patient
department, 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 pre-treatment or with diVerent 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 3 years and 1 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 mg once a
week. A further selection criterion was initial prescription
of 1,200 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 speciWc drug therapy (non-bisphosphonates) during the 1 year of follow-up. Switching to a
generic or another branded original bisphosphonate in
group B or C during the 1 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 was available in the patient charts. In Table 1 the initial characteristics of the 186 patients who fulWlled all above criteria are
given. 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

215
Table 1 Baseline characteristics of patients

Number of patients (n)

Gen. Aln.

Fosamax

Actonel

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

Patients with prevalent

vertebral fractures, n (%)

35 (56)

38 (61)

41 (66)

Patients with prevalent

non-vert-fractures n (%)

17 (27)

19 (31)

20 (32)

No signiWcant diVerence between groups

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 their drug regimen. Compliance was determined asking the patient how they took their osteoporosis
medication and if they took it on time. Patients verbal
feedback regarding compliance and persistence was rated
and coded in the clinical record.
Statistical methods
One hundred and eighty six of the 204 women with postmenopausal osteoporosis who fulWlled 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 two-sided at the
5% level of signiWcance.

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 group B [Branded
Alendronate (Fosamax) 70 mg] and 94% of group C
[Branded Risedronate (Actonel) 35 mg]. The persistence
of patients treated with Generic Alendonate 70-mg products was signiWcantly lower as compared to each of the two
original branded BP treated groups (Fig. 1). Corresponding
to these Wndings the persistence with calcium vitamin D
supplementation was also lower in group A than in groups
B and C.

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Rheumatol Int (2009) 30:213221

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

*All patients (ITT population)

Fosamax
(n = 62)

Gen. Aln.
(n = 62)
Patients still on BP at month 12, n (%)

40 (68)

52 (84)

58 (94)

Mean duration of (m) intake of BP*

9.5

11.0

11.6

Patients still on Ca/D at month 12 n (%)

43 (73)

51 (82)

52 (84)

Mean duration of (m) intake of Ca/D

8.8

10.2

10.7

Table 3 Number of patients with gastrointestinal adverse events

during the 12-month follow-up period

100
90
80
70
60
50
40
30
20
10
0

Fosamax
(n = 62)

Gen. Aln.
(n = 62)
A: Gen. Aln.
B: Fosamax
C: Actonel

BP-Comliance

Ca./Vit. D
Compliance

BP: A vs B p< 0.03, A vs C p<0.01 Ca/D: A vs B and C p< 0.05

Fig. 1 Persistence with bisphosphonate therapy and calcium/vitamin

D supplementation (% patients at month 12)

Adverse events
During the 12 months of observation gastrointestinal
adverse events were documented in 32 patients with
Generic Alendonate 70-mg product 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 signiWcantly higher
in Group A. Other non-gastrointestinal AEs were observed
in 14 patients of group A, 9 and 5 respectively in groups B
and C (Table 4). Only the diVerence between generic
alendronates and branded Risedronate (Actonel) 35 mg
was statistically signiWcant (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 (Fig. 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 diVerent between the two
groups receiving original branded BPs (B, C) but for both
signiWcantly higher than for group A treated with generic
Alendonate 70-mg products (Fig. 2).

123

Actonel
(n = 62)

Actonel
(n = 62)

Mild epigastric discomfort

Epigastric pain

1
3

Esophageal burning

Nausea

Vomiting

Diarrhea

Obstipation

Meteorism

All GI adverse events

32*

15

*versus Fosamax p < 0.05, versus Actonel p < 0.01

Table 4 Number of patients with non-gastrointestinal adverse events

during the 12-month follow-up period
Gen. Aln.
(n = 62)

Fosamax
(n = 62)

Actonel
(n = 62)

Arthralgia

Bone pain

Muscle cramps

Headache

Dizziness

Vertebral Fx

Non-vertebral Fx
All other AE*

14

Vertebral and non-vertebral Fx were captured as AE (i.e. clinical Fx)

*Gen. Aln. versus Fosamax non signiWcant, Fosamax versus Actonel non signiWcant, Gen. Aln. versus Actonel p < 0.05

Discussion
The total number of patients reporting gastrointestinal
events was signiWcantly higher in patients treated with
generic Alendonate 70 mg once-weekly products than with
the two branded original bisphosphonate-treated patients.
Data analysis shows after 12 months signiWcantly higher
average BMD increases at lumbar spine and at total hip for

Rheumatol Int (2009) 30:213221

217

Smaller increases in BMD due to lower persistence

as a consequence of a higher rate of adverse events

6
5
4
A: Gen. Aln.

B: Fosamax
C: Actonel

2
1
0
LS

TH

LS: A vs B and C p< 0.05 TH: A vs B and C p< 0.01

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

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 signiWcantly higher incidence in gastro-intestinal
adverse events with generic alendronates has been published (30), this is the Wrst report demonstrating a signiWcantly lower increase of lumbar spine and total hip bone
mineral density after 1 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 1 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 (Fig. 2). In our study the persistence of
patients treated with generic Alendonate 70 mg once
weekly products was signiWcantly lower as compared to
each of the two with branded original bisphosphonatetreated patient groups.
What could be possible explanations for these signiWcant
diVerences 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 diVerences 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?
5. A combination of any of the previous four-ones?

Since a signiWcantly lower persistence with generic bisphosphonates was shown in our study (Fig. 1), this may be
indeed the major factor leading to the highly signiWcant
lower increases in BMD at both measuring sites. DiVerent
studies in recent years proved signiWcant correlations
between compliance and therapeutic results during bisphosphonate therapy [26, 34, 35]. It was shown that noncompliance with antiresorptive therapies has been
associated with a 1650% increased risk of fracture [26,
3438]. 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 signiWcantly stronger eVect on fracture risk than those with poor
compliance [26, 27, 37].
Lower bioavailability and higher rate of adverse events due
to diVerences 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 [79,
32, 33, 3946]. Two recent studies have shown diVerences
in tablets properties that might explain diVerent 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 diVerent Generic Alendronate
copies from Canada, Germany, the Netherlands, and UK
[47]. The mean disintegration times of the generic alendronate tablets in vitro ranged from 14 to 342 s (5.7 min) [47].
The mean disintegration time of the branded product tablets
(Actonel and Fosamax) ranged only from 43 to 78 s [47].
Six of the 26 companies market alendronic acid tablets having very rapid disintegration times which are similar to
those of orally disintegrating tablets (non-bisphosphonates)
[47]. 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 [47].
Another trial evaluated and compared esophageal transit
times and in vivo disintegration of one branded risedronate
and two generic formulations of alendronic acid tablets [48]
that are commercially available in Canada and the United
Kingdom. It was shown that the two generic formulations of

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alendronic acid tablets had signiWcant slower transit times

than compared with the branded risedronate (Actonel) tablet tested [48]. The branded risedronate tablet had a signiWcantly faster transit time than the two generic formulations
of alendronate tested [48]. 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. DiVerent formulations of
generic bisphosphonate tablets meeting regulatory requirements may have substantial diVerences in pharmaceutical
attributes from the branded product that may result in diVerent characteristics during esophageal transit. A potential
concern is that the pharmaceutical attributes of the various
copy alendronate formulations may aVect the potential for
local irritation and tolerability, especially in the upper gastrointestinal tract. Epstein et al. [49] 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, PetahTikva, Israel) compared to the branded innovator product
(Alendronate sodium tablets, 10 mg). The diVerences 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 proWles 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 [50]. From an eYcacy perspective, Epstein
et al. also concluded that tablets that disintegrate faster than
branded Alendronate sodium tablets (1.4 min) could result
in reduced eYcacy 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 eYcacy of some
generic Alendronate products due to very short disintegration times of the tablets (and a signiWcant slower esophageal
transit time of Generic 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 eYcacy in terms of BMD
increases not reached. The diVerence in the gastrointestinal
safety and tolerability proWle in favor for Risedronate versus
Alendronate could together with the inferior disintegration

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Rheumatol Int (2009) 30:213221

and dissolution characteristics and signiWcant slower esophageal transit time of once weekly generic Alendronate tablets explain the higher rates of gastrointestinal adverse
events and lower eYcacy 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 proWle of Alendronate compared to
Risedronate would become even worse due to diVerences in
disintegration and dissolution properties and a signiWcant
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 eYcacy 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-BPs like Risedronate or Alendronate is the
correct intake. Bioavailability of oral bisphosphonates is
poor due to low intestinal absorption rates [51]. 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 [52].
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. Noncompliance 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 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 eVective 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
diVerences in compliance and persistence and, therefore,

Rheumatol Int (2009) 30:213221

eYcacy. It cannot be excluded that besides adverse events

psychological factors may also contribute to a reduced persistence with generic alendronates. The knowledge about being
treated with generics may have an inXuence on patients
behavior. 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 signiWcantly more adverse events during the
second treatment phase although the patients were unaware of
having been switched to generics [30].
Study limitations
The present retrospective single center-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 [53]. On the other hand, in our
study there were no statistical diVerences in measurable
patient characteristics among the three cohorts of patients at
initiation of therapy. The strength of this study is 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 patients level of present understanding of the
dosing instructions, compliance, and persistence but cannot
truly represent the respondents previous behavior 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 diVerences
between the two in relation to expertise of health care provider, quality of medical care, course of therapy, and types
of patients [54]. 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 [55].

Summary and conclusions

SigniWcantly 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 4050% lower BMD
increased rates when using the generic compounds are not

219

known yet. At least in part the lower eYcacy can be

explained by a signiWcantly 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 eVectiveness when prescribing generic alendronate are urgently
needed.
Acknowledgments 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 patients
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 PharmaceuticalsGermany GmbH, Lilly Deutschland, SanoW-Aventis Deutschland GmbH. Gerd Mller, MD, PhD, Health Economist (ebs) was an
employee of Procter & Gamble PharmaceuticalsGermany GmbH,
D-65824 Schwalbach am Taunus, Germany from May 15th 2001 until
September 5th 2008. Gerd Mller, MD, PhD, Health Economist (ebs)
received no consultancy fees and other payments from any pharmaceutical company.

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