Osteoporos Int (1999) 9:461–468
ß 1999 International Osteoporosis Foundation and National Osteoporosis Foundation
Osteoporosis
International
Original Article
Multinational, Placebo-Controlled, Randomized Trial of the Effects of
Alendronate on Bone Density and Fracture Risk in Postmenopausal
Women with Low Bone Mass: Results of the FOSIT Study
H. A. P. Pols1, D. Felsenberg2, D. A. Hanley3, J. Štepán4, M. Muñoz-Torres5, T. J. Wilkin6,
G. Qin-sheng7, A. M. Galich8, K. Vandormael9, A. J. Yates10 and B. Stych11 for the Fosamax1
International Trial Study Group
1
Erasmus University Medical School, Rotterdam, The Netherlands; 2Free University of Berlin, Berlin, Germany; 3University of
Calgary, Calgary, Alberta, Canada; 4Charles University, Prague, Czech Republic; 5Hospital Clinico San Cecilio, Granada, Spain;
6
Freedom Fields Hospital, Plymouth, Devon, UK; 7Peking Union Medical College Hospital, Beijing, People’s Republic of China;
8
Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; 9Merck Research Laboratories, Brussels, Belgium; 10Merck
Research Laboratories, Rahway, New Jersey, USA; 11Merck & Co., Inc., Whitehouse Station, New Jersey, USA
Abstract. This randomized, double-masked, placebocontrolled trial evaluated the safety, tolerability and
effects on bone mineral density (BMD) of alendronate in
a large, multinational population of postmenopausal
women with low bone mass. At 153 centers in 34
countries, 1908 otherwise healthy, postmenopausal
women with lumbar spine BMD 2 standard deviations
or more below the premenopausal adult mean were
randomly assigned to receive oral alendronate 10 mg
(n = 950) or placebo (n = 958) once daily for 1 year. All
patients received 500 mg elemental calcium daily.
Baseline characteristics of patients in the two treatment
groups were similar. At 12 months, mean increases in
BMD were significantly (p40.001) greater in the
alendronate than the placebo group by 4.9% (95%
confidence interval 4.6% to 5.2%) at the lumbar spine,
2.4% (2.0% to 2.8%) at the femoral neck, 3.6% (3.2% to
4.1%) at the trochanter and 3.0% (2.6% to 3.4%) for the
total hip. The incidence of nonvertebral fractures was
significantly lower in the alendronate than the placebo
group (19 vs 37 patients with fractures), representing a
Correspondence and offprint requests to: Huibert A. P. Pols,
MD, PhD, Department of Internal Medicine III, Erasmus
University Medical School, PO Box 1738, 3000 DR Rotterdam, The
Netherlands. Tel: +31 10 4635956. Fax: +31 10 4633268. e-mail:
pols@epib.fgg.eur.nl.
Fosamax1 is a registered trademark of Merck & Co., Inc.,
Whitehouse Station, NJ, USA.
47% risk reduction for nonvertebral fracture for
alendronate-treated patients (95% confidence interval
10% to 70%; p = 0.021). Incidences of adverse events,
including upper gastrointestinal adverse events, were
similar in the two groups. Therefore, for postmenopausal
women with low bone mass, alendronate is well
tolerated and produces significant, progressive increases
in BMD at the lumbar spine and hip in addition to
significant reduction in the risk of nonvertebral fracture.
Keywords: Alendronate; bisphosphonate; Bone mineral
density; Fractures; Postmenopausal osteoporosis
Introduction
Osteoporosis is characterized by low bone mass and
microarchitectural deterioration of bone with consequent
bone fragility and thus an increased risk of fracture, most
commonly vertebral, wrist (Colles’) and hip fractures
[1,2]. Osteoporosis in postmenopausal women is an
important public health issue in industrialized countries.
A 50-year-old white woman has a 40% risk of
experiencing a clinically apparent fracture during her
remaining lifetime [3]. In the United States and Europe,
approximately 30% of all postmenopausal white women
have osteoporosis, as defined by bone mineral density
(BMD) measurements [1]. This high prevalence of
462
osteoporosis occurs because of low postmenopausal
estrogen levels, which result in progressive bone loss
secondary to a combination of increased bone turnover
and an excess of bone resorption relative to bone
formation [4].
Alendronate, a potent inhibitor of osteoclast-mediated
bone resorption, normalizes the rate of bone turnover to
premenopausal levels [5]. In both animal and human
studies administration of alendronate increases bone
mass and maintains histologically normal bone [6–9].
Liberman and colleagues [10] reported that treatment
with 10 mg alendronate daily for 3 years resulted in
mean increases, relative to placebo, of 8.8%, 5.9% and
7.8% in BMD of the lumbar spine, femoral neck and
trochanter, respectively, in addition to marked decreases
in vertebral and nonvertebral fracture incidence among
approximately 200 women with osteoporosis.
The objective of the current double-masked, placebocontrolled study was to evaluate efficacy and tolerability
of alendronate over 1 year in a large and diverse
multinational population of postmenopausal women with
low bone mass.
Patients and Methods
Patients
We recruited patients from 153 centers in 34 countries
(in Europe, Latin America, Australia, Canada, South
Africa and China). Women eligible for study participation had been postmenopausal for at least 3 years, were
not older than 85 years, and had BMD of the lumbar
spine (L2–4) at least 2 standard deviations (SD) below
the mean for mature, premenopausal women – a value
that approximately corresponds to the median BMD of
65-year-old women. Lumbar spine BMD, as measured
using dual-energy X-ray absorptiometry (DXA), was
40.86 g/cm2 by Hologic QDR densitometry (Hologic,
Waltham, MA) or 40.98 g/cm2 by Lunar DPX
densitometry (Lunar, Madison, WI). Eligible patients
were otherwise in good health and were between 20%
below and 50% above ideal body weight as defined in
the Metropolitan Life Insurance Company Height and
Weight Table. Levels of 25-hydroxyvitamin D were
determined before study entry.
Excluded from participation were women with
metabolic bone disease other than postmenopausal
osteoporosis; disturbed parathyroid or thyroid function;
major gastrointestinal disease (for example, peptic ulcer
or malabsorption) within the year before enrollment or
use of a drug to inhibit gastric acid secretion for >2
weeks within 3 months of study entry; myocardial
infarction within the year prior to enrollment; uncontrolled hypertension or untreated angina; significantly
impaired renal function (serum creatinine >150 mmol/l);
or evidence of significant end organ disease. Also
excluded were women who had received a bisphosphonate or fluoride (>8 mg/day) during the previous 6
months; estrogen (except vaginal 43 times/week),
H. A. P. Pols et al.
ipriflavone or calcitonin during the previous 4 months;
or any anabolic steroid, glucocorticoid or progestin for
>2 weeks within the previous 6 months. Participants
could not be receiving any medications that might alter
bone or mineral metabolism, including vitamin A in
excess of 10.000 U/day, vitamin D in excess of 1000
U/day, anticonvulsants or phosphate-binding antacids.
Finally, at least three vertebrae from L1 to L4 had to be
evaluable by DXA to determine BMD in this region.
Spinal radiographs were not obtained before study entry.
The study protocol was approved by each local ethics
committee, and all participants signed a written informed
consent form.
Study Design
After a 2- to 4-week baseline period, study participants
were randomly assigned to receive alendronate 10 mg or
matching-image placebo tablets once daily for 12
months. Patients were instructed to take one tablet of
study drug with a glass of water each morning, after an
overnight fast, and to refrain from lying down or taking
any other beverage or food for at least 30 min thereafter.
All patients received tablets containing 500 mg of
elemental calcium as the carbonate or citrate salt with
instructions to take one tablet daily at the evening meal.
Efficacy Criteria
Bone densitometry was performed during the baseline
period and at 3, 6 and 12 months after starting the study
drug. BMD was measured, using Hologic QDR
densitometers (QDR-1000, -1000/W, -1500 or -2000;
Hologic, Waltham, MA) or Lunar DPX densitometers
(DPX, DPX-L or DPX-a; Lunar, Madison, WI), at the
following four sites: lumbar spine (primary endpoint),
femoral neck, trochanter and total hip. The mean BMD
from at least three evaluable vertebrae from L1 to L4
was used to determine lumbar spine BMD. All BMD
measurements were reviewed at a central quality
assurance site.
Bone-specific alkaline phosphatase, a marker of bone
formation, and urine N-telopeptide crosslinks of type I
collagen/creatinine ratio, a marker of bone resorption,
were measured at each clinic visit using previously
described assays [11,12]. Assays were performed at a
central laboratory.
Safety Criteria
Adverse events were recorded at each visit using
nonleading questioning. An electrocardiogram and
complete physical examination (repeated at 12 months)
were performed at the screening visit; limited physical
examinations were performed at subsequent visits.
Clinical laboratory tests were performed at each visit.
The occurrence of clinical fractures was captured
through adverse event reporting. To evaluate whether all
fractures had been correctly coded by the investigators,
Effects of Alendronate on BMD and Fracture Risk: The FOSIT Study
supporting documentation for each fracture consisting of
radiographs and/or radiology reports, hospital discharge
reports with clinical diagnosis and/or confirmation by the
investigator/treating physician was sought after completion of the study.
463
percentage change from baseline in BMD of the lumbar
spine, assuming a standard deviation of 4.5%. All
treatment comparisons were two-sided, and statistical
significance was defined as p40.05.
Results
Statistical Methods
The primary evaluation of the efficacy data was based on
the intention-to-treat principle. The effect of treatment
on BMD and biochemical markers of bone turnover was
assessed using analysis of variance with factors for
treatment and center.
Fisher’s exact test was used to compare the incidence
of adverse events. The analysis of clinical fracture
incidence as an efficacy parameter, which was not
predefined because of limited power, was based on the
log rank test. The estimate of the relative hazard was
derived from a proportional hazards model by the
likelihood ratio method. Sensitivity and subgroup
analyses were performed to evaluate the robustness
and consistency of results.
The study had 599% power to detect a 3.5%
difference between alendronate and placebo in mean
Of 1908 randomized patients, 950 were assigned to
treatment with alendronate and 958 to placebo. The two
treatment groups were comparable with regard to patient
demographic characteristics, BMD and biochemical
markers of bone turnover at baseline (Table 1); 94% of
randomized patients in each group were white. A total of
1697 (89%) patients completed the study: 832 (88%) in
the alendronate groups and 865 (90%) in the placebo
group.
Bone Mineral Density
Marked and progressive mean increases in BMD were
recorded for alendronate-treated patients. Table 2
presents changes from baseline in BMD at 12 months.
At all sites and at each time point, including at 3 months,
Table 1. Baseline characteristics of randomized patients
Age in years
Mean (SD)
Median (range)
Mean (SD) years postmenopausal
Mean (SD) weight in kg
Mean (SD) height in cm
Mean (SD) bone mineral density in g/cm2
Lumbar spine (Hologic QDR)
Lumbar spine (Lunar DPX)
Femoral neck (Hologic QDR)
Femoral neck (Lunar DPX)
Trochanter (Hologic QDR)
Trochanter (Lunar DPX)
Total hip (Hologic QDR)
Mean (SD) bone-specific alkaline phosphatase in ng/ml
Mean (SD) urine N-telopeptide/creatinine in pmol
BCE/mmol
Placebo
(n = 958)
Alendronate 10 mg
(n = 950)
62.8
63.0
15.9
63.6
158.5
62.8
63.0
15.8
63.8
158.6
0.72
0.83
0.62
0.76
0.55
0.64
0.73
13.1
63.1
(7.4)
(40–82)
(8.4)
(9.7)
(6.8)
(0.08)
(0.09)
(0.08)
(0.12)
(0.08)
(0.11)
(0.10)
(4.9)
(33.7)
0.72
0.84
0.63
0.75
0.55
0.65
0.73
13.0
60.7
(7.5)
(39–84)
(8.5)
(9.6)
(7.0)
(0.08)
(0.08)
(0.09)
(0.10)
(0.08)
(0.10)
(0.10)
(5.0)
(34.7)
BCE, bone collagen equivalent.
Table 2. Mean percentage change from baseline in bone mineral density as measured by dual-energy X-ray absorptiometry
after 1 year of treatment with alendronate 10 mg or placebo
Placebo
Lumbar spine
Femoral neck
Trochanter
Total hip
Alendronate 10 mg
n
Mean
(SD)
n
Mean
(SD)
903
884
884
537
70.1
70.2
70.4*
70.1
(3.4)
(4.5)
(4.6)
(3.0)
877
863
863
527
5.00**
2.3**
4.1**
3.1**
(3.2)
(4.5)
(5.2)
(3.5)
p<0.001 for all between-group comparisons.
*p<0.01 compared with baseline; **p<0.001 compared with baseline.
464
H. A. P. Pols et al.
Fig. 1. Mean percentage changes from
baseline and 95% confidence intervals for
bone mineral density of the lumbar spine
in women receiving alendronate 10 mg or
placebo for 1 year (p50.001 for betweengroup comparisons at 3, 6 and 12
months).
mean percentage changes in BMD among patients in the
alendronate group were significantly (p<0.001) greater
than those among patients in the placebo group; changes
at the lumbar spine are illustrated in Fig. 1. At 12 months
the difference in least square means between alendronate
and placebo groups in percentage changes from baseline
in BMD was 4.9% (95% confidence interval 4.6% to
5.2%) at the lumbar spine, 2.4% (2.0% to 2.8%) at the
femoral neck, 3.6% (3.2% to 4.1%) at the trochanter and
3.0% (2.6% to 3.4%) for the total hip.
The treatment-by-center and treatment-by-densitometer-type interactions were not significant, indicating
that the treatment effect on BMD was consistent among
investigators and independent of densitometer type.
Biochemical Markers of Bone Turnover
with 37 patients receiving placebo. The cumulative
incidence of patients experiencing nonvertebral fracture
is plotted in Fig. 2. The estimated cumulative incidence
of nonvertebral fracture after 1 year was 2.4% in the
alendronate group and 4.4% in the placebo group,
yielding a relative hazard of 0.53 (95% confidence
interval, 0.30 to 0.90). Figure 3 shows the percentage of
women treated with alendronate or placebo, by fracture
site, who experienced each specific type of nonvertebral
fracture.
In all cases except one there was clear clinical or
radiographic evidence, or both, supporting a definite
fracture at the time the fracture was reported. The
exception was a placebo-treated patient for whom the
radiology report indicated that a malleolar fracture could
not be excluded, but the radiograph did not allow for a
definitive diagnosis. Analysis of the data excluding this
Both bone-specific alkaline phosphatase and urine Ntelopeptide/creatinine decreased significantly (p<0.001)
compared with baseline in the alendronate and placebo
groups (alkaline phosphatase by 52% vs 11%, respectively, and urine N-telopeptide/creatinine by 74% vs
21%, respectively, at 12 months). For both parameters,
decreases were significantly (p<0.001) greater in the
alendronate group than in the placebo group at all time
points (data not shown). The reductions seen in the
placebo group reflect the antiresorptive effect of
calcium.
Clinical Features
The risk of clinical nonvertebral fracture was significantly (p = 0.021) lower in the alendronate group than in
the placebo group: 19 patients receiving alendronate
experienced at least one nonvertebral fracture compared
Fig. 2. Cumulative proportion of patients with any clinical
nonvertebral fracture. Alendronate treatment for 1 year was associated
with a 47% reduction in the risk of nonvertebral fracture relative to
placebo (95% confidence interval, 10% to 70%; p = 0.021).
Effects of Alendronate on BMD and Fracture Risk: The FOSIT Study
465
Fig. 3. Percentage of patients receiving alendronate 10 mg or placebo for 1 year with clinical nonvertebral fractures at specified sites.
fracture continued to support a significant reduction in
nonvertebral fractures (p = 0.028). Since spine radiographs were not obtained before study entry, it was not
possible to be certain that a compressed vertebra
observed during the study represented a new fracture
as opposed to a pre-existing fracture. Vertebral fractures,
therefore, could not be evaluated.
resulting in hospitalization or permanent disability or
cancers, were also equally common between groups
(alendronate 6.5%; placebo 6.3%).
There were no significant differences between
treatment groups in the overall incidence of upper
gastrointestinal adverse events (alendronate, 21.3%;
placebo, 19.3%) or of specific upper gastrointestinal
adverse events such as abdominal pain, dyspepsia, or
nausea or esophageal events (Table 3).
Safety and Tolerability
Discussion
Alendronate was generally well tolerated. No statistically significant differences between treatment groups
were found in the overall incidence of adverse events
(alendronate, 67.1%; placebo, 69.7%), the incidence of
adverse events considered by the investigator to be
possibly, probably or definitely drug-related (19.1% vs
18.0%), or the incidence of adverse events resulting in
permanent discontinuation of study medication (6.4% vs
5.6%). Serious adverse events, specifically those
One year of treatment with alendronate produced
significant and progressive increases in BMD among
patients enrolled in this large, multinational study. The
effects observed were independent of study center.
The increases recorded in BMD at the spine and hip
are very similar to those observed with alendronate 10
mg at 12 months in previous studies. The weighted
average effect on lumbar spine BMD in patients from
Table 3. Patients reporting upper gastrointestinal adverse events
Any upper gastrointestinal adverse event
Abdominal pain
Nausea
Gastritis/gastroenteritis
Acid regurgitation
Dyspepsia
Vomiting
Esophagitis
Reflux esophagitis
Gastric ulcer
Dysphagia
Duodenal ulcer
Esophagalgia
Odynophagia
Esophageal stricture
Placebo
(n = 958)
Alendronate 10 mg
(n = 950)
185
81
37
20
24
22
24
5
3
1
2
3
0
1
0
202
95
44
26
22
24
17
4
4
4
1
0
2
0
1
(19.3%)
(8.5%)
(3.9%)
(2.1%)
(2.5%)
(2.3%)
(2.5%)
(0.5%)
(0.3%)
(0.1%)
(0.2%)
(0.3%)
(0.1%)
No between-group comparisons were statistically significant,
(21.3%)
(10.0%)
(4.6%)
(2.8%)
(2.3%)
(2.5%)
(1.8%)
(0.4%)
(0.4%)
(0.4%)
(0.1%)
(0.2%)
(0.1%)
466
four previous clinical, randomized studies [10,13,14]
was 5.06%, which is highly comparable to the mean
5.00% observed in this study (unpublished data on file,
Merck & Co., Inc.). The consistency of response across
studies is remarkable when the differences in geography
(USA only, or multinational excluding USA) and patient
definition are considered.
A major finding in this study is that alendronate 10 mg
was associated with a significant decrease in the
incidence of nonvertebral fractures over just 1 year of
treatment. At the time this study was initiated there were
no data available on potential fracture risk reduction
associated with alendronate treatment. It was considered
unlikely that a significant difference in clinical fractures
could be demonstrated in such a short time period, as the
expected number of events was low. Therefore, there
was no formal hypothesis that nonvertebral fracture
incidence would be reduced. Since that time, other
alendronate studies have demonstrated decreases in
vertebral and nonvertebral fracture incidence, albeit
over a longer period of study. In each of these previous
studies, time-to-event plots demonstrated a lower
incidence of fractures in the alendronate group over
the entire duration of the study (including the 1-year
time point), although significance at 1 year has not
previously been reported [10,15,16]. Moreover, the
fracture incidence in the placebo group in this study
was similar to that seen in prior studies. Therefore, the
consistency of these data across studies provide
compelling evidence to support fracture reduction with
alendronate, even within the first year of therapy.
The fact that all patients in the current study received
the dose of alendronate that produces optimal effects on
BMD (10 mg) from the outset may have contributed to
the substantial (47%) risk reduction for nonvertebral
fractures.
A limitation of the current study is that fractures were
captured through adverse event reporting only and no
vertebral radiographs were obtained; thus, the impact on
radiographically (or morphometrically) defined vertebral
fractures could not be assessed. However, the fact that
the study population represents patients with BMD 2 SD
or more below the young adult means without regard to
presence or absence of previous vertebral fractures is in
itself important to the generalizability of the results.
Moreover, the findings of the current study are consistent
with those of a meta-analysis of five prospective,
randomized, placebo-controlled studies of alendronate
treatment of osteoporosis, which found a 29% reduction
in risk of nonvertebral fracture in patients treated with
doses of 52.5 mg/day alendronate for 2 years or more
[16].
Compared with previous alendronate trials, the
subjects in the current study represent a relatively
unselected group of patients, recruited on the basis of
low bone mass without regard to history of vertebral
fracture. The vertebral fracture arm of the Fracture
Intervention Trial [15] enrolled 2027 women with low
BMD and pre-existing vertebral fractures at baseline.
These women constitute a very high-risk population, as
H. A. P. Pols et al.
the presence of a vertebral fracture greatly increases the
risk of future hip and vertebral fractures [17,18]. In the
Fracture Intervention Trial, administration of alendronate 5 mg for 2 years followed by 10 mg in the third year
reduced the incidence of morphometrically measured
vertebral fracture by 47% and of any clinical fracture by
28%.
Alendronate was well tolerated in the present study.
Adverse events (other than fractures), including upper
gastrointestinal adverse events, occurred with similar
incidence in the alendronate and placebo groups, a
finding that is consistent with earlier studies [10,13–15].
This finding is, however, in contrast to the perception
that alendronate may cause upper gastrointestinal
complaints more frequently in general practice. One
important consideration is that upper gastrointestinal
complaints are common in the general population,
particularly among women of this age range. Indeed,
approximately 20% of patients in this study had
complaints whether they were on placebo or alendronate,
which is consistent with the incidence reported in a
population-based survey in the USA [19].
Although there have been occasional reports of
esophagitis associated with alendronate [20], no excess
in esophageal adverse events was found in the present
study. Moreover, patients were not excluded from the
study for a history of gastrointestinal disease, excepting
those with major gastrointestinal disease during the past
year. All study participants were instructed to take study
medication with a full glass of water and to refrain from
lying down for 30 min afterwards, consistent with the
recommendations in the product label.
We conclude that alendronate is well tolerated and
produces significant and progressive increases in BMD
at both the lumbar spine and hip among a diverse
population of postmenopausal women with osteoporosis
defined on the basis of low spine BMD without regard to
prior fracture history. This is the first study in which
treatment with 10 mg alendronate is associated with a
significant reduction in nonvertebral fracture after only 1
year of therapy.
Appendix. The FOSIT Study Group
Argentina: R. Gutman, A. Galich, Hospital Italiano,
Buenos Aires.
Australia: J. Wark, P. Ebeling, Royal Melbourne
Hospital, Victoria; M. Hooper, Concord Hospital,
Sydney; D. Perry-Keene, Royal Brisbane Hospital,
Queensland.
Austria: K. Klaushofer, G. Fellinger, Hanusch-Krankenhaus, Vienna; F. Skrabal, Krankenhaus der Barmherzigen Brüder, Graz; G. Galvan, H. Kässmann,
Landeskrankenanstalten, Salzburg; G. Schernthaner, H.
Woschnagg, Krankenanstalt der Stadt Wien Rudolfstiftung, Vienna; G. Leb, A. Fahrleitner, Medizinische
Universitätsklinik, Graz; R. Kotz, Allgemeines Krankenhaus, Vienna; J. Smolen, Krankenhaus der Stadt Wien
Lainz, Vienna.
Effects of Alendronate on BMD and Fracture Risk: The FOSIT Study
Belgium: M. Fuss, Hôpital Brugmann, Brussels; B.
Pornel, Brussels Menopause Center, Brussels; J. Body,
Institut Bordet, Brussels; J. Bentin, Hôpital Louis Caty,
Baudour; M. Malaise, Centre Hospitalier, Liège.
Brazil: V. Sjeznfeld, Hospital São Paulo, Sao Paulo; C.
Zerbini, Hospital Heliopolis, São Paulo; L. Griz,
Hospital Agamenon Magalhaes, Recife.
Canada: D. Hanley, University of Calgary Health
Science Center, Calgary; D. Kendler, Vancouver
Hopital/Health Science Center, Vancouver; W. Sturtridge, Toronto General Hospital, Toronto; L. Ste-Marie,
Hôpital St-Luc, Montreal; A. Tenenhouse, Montreal
General Hospital, Montreal; W. Olszynski, Midtown
Medical Center, Saskatoon.
China: G. Quin-Sheng, S. Qing Lin, Peking Union Med
College Hospital, Beijing.
Colombia: A. Nino, Clinica Palermo; A. Iglesias, R.
Martinez, Universidad Nacional de Colombia, Bogata.
Costa Rico: F. Bermudez-Cordero, A. Cob, Hospital San
Juan de Dios, San José.
Croatia: M. Korsic, University Hospital Center Zagreb,
Zagreb.
Czech Republic: J. Stephan, J. Vokrouhlicka, 1st
Medical Faculty of Charles University, Prague.
Denmark: E. Eriksen, H. Glerup, Arhus Amtssygehus;
O. Sorensen, C. Brot, Kommunehospitalet, Copenhagen.
Finland: J. Salmi, T. Piippo, Tampereen Laakarikeskus
Ky, Tampere; E. Alhava, H. Kroger, I. Arnala, J.
Huuskonen, Kuopion Yliopistollinen Sairaala, Kuopio;
J. Viikari, M. Kormano, V. Salonen, Turun Laakariasema Vagus Oy, Turku; P. Salmela, H. Pirttiaho, J.
Heikkinen, Oulun Diakonissalaitos, Oulu; M. Valimaki,
A. Viitanen, Helsingin Laakarikeskus, Helsinki.
Germany: T. Seppel, Heinrich-Heine-Universität, Duesseldorf; D. Felsenberg, Universitätsklinik Benjamin
Franklin, Berlin; C. Kerber, Klinikum Schwerin,
Schwerin; A. Knauerhase, Universität Rostock, Rostock;
J. Schuhmacher, Lüneburg; P. Schneider, Luitpoldkrankenhause, Würzburg; F. Dahl, Lüneburg; J. Happ,
Frankfurt; B. Allolio, Universität Würzburg; D. Sabo,
Orthopädische Universitätsklinik Radiologie, Heidelberg; J. Semler, Immanuel Krankenhause GmbH,
Berlin; K. Moerike, Magdeburg; G. Meurers, Krankenhaus Vinzentinum, Ruhpolding; E. Lemmel, Staatl
Rheumakrankenhaus, baden-Baden; J. Ittner, Augsburg;
M. Hofmann, Schwandorf; J. Boehm, Straubing; H.
Kruse, Universitätsklinik Eppendorf, Hamburg; P.
Donhauser, Ludwig-Maximillian Universität, Munich;
M. Balz, Taufkirchen; M. Fischer, Städtische Kliniken,
Kassel; H. Haentzschel, Universität Leipzig, Leipzig; H.
Hitzler, Bochum; W. Liman, Evangelisches Krankenhaus, Hagen; W. Spieler, Krankenhaus Vogelsang,
Vogelsang; H. Herberling, Städtische Klinik Leipzig,
Leipzig.
Greece: G. Tolis, Ippokration Hospital, Athens; M.
Anapliotou, Laiko Hospital, Athens; K. Phenekos,
Erythros Stavros Hospital, Athens; G. Lyritis, Kath
Hospital, Klfisia; P. Kaldrimidis, Metaxa’s Hospital,
Piraues; A. Avramides, Hippokratio Hospital, Thessaloniki.
467
Holland: W. Reitsma, Academisch Ziekenhuis, Groningen; J. Juttmann, St Elisabeth Ziekenhuis, Tilburg; A.
Smals, Academisch Ziekenhuis, Nijmegen; H. Van der
Wiel, IJsselland Ziekenhuis, Cappelle; H. Pols, Academisch Ziekenhuis Dijkzicht, Rotterdam; F. Van Berkum,
Streekziekenhuis Hengelo, Hengelo; P. Lips, Academisch Ziekenhuis VU, Amsterdam; A. Van de Wiel, De
Lichtenberg, Amersfoort; B. Wolffenbuttel, Academisch
Ziekenhuis Maastricht, Maastricht.
Hungary: A. Balogh, University Medical School
Debrecen, Debrecen.
Iceland: G. Sigurdsson, Borgarspitalinn, Reykjavik.
Israel: S. Ish-Shalom, Rambam Medical Center, Haifa; I.
Vered, Sheba Medical Center, Tel Hashomer; M. Weiss,
Wolfson Medical Center, Holon; M. Hirsch, Bellinson
Medical Center, Petach Tikva.
Lebanon: G. Maalouf, St George’s Hospital, AshrafiehBeirut.
Luxembourg: P. Hemmer, M. Hirsch, Luxembourg.
Mexico: L. Sanchez, Instituto Mexicano del Seguro
Social Siglo XXI, Mexico City; A. Valero, Hospital
Angeles del Pedregal, Mexico City; P. Garcia Hernandez, Hospital Universitario de Monterrey, Monterrey; F.
Flores-Lozano, Hospital Angel Leano, Guadalajara.
Norway: M. Gunnes (in memoriam), J. Stakkestad,
Cecor AS, Haugesund; A. Hoiseth, A. Andreassen,
Sentrum rontgen institutt, Oslo; E. Ofjord, A. Skag,
Bergen Osteoporosesenter, Fjosanger; I. Omsjo, E.
Giske, Osteoporoselaboratoriet A/S, Oslo; S Hemminghytt, Spesialistgruppen, Bodo; J. Halse, Betanien Med
Labs, Oslo.
Peru: J. Zaidman, O. Espinoza, Clinica Ricardo Palma,
Lima; J. Angulo Solimano, Hospital de la Fuerza Aerea,
Lima.
Poland: S. Zglyczynski, W. Misiorowski, Postgraduate
Medical School, Bielanski Hospital, Warsaw.
Portugal: A. Lopes Vaz, Hospital de S. Joao, Porto; C.
Da Silva, Hospital Garcia da Orta, Almada; A. Alves de
Matos, Hospital Egas Moniz, Lisbon; V. de Queiroz,
Hospital de Santa Maria, Lisbon; A. Porto, Hospital de
Universidad de Coimbra, Coimbra.
Russia: L. Benevolenskaya, T. Spiritus, Research
Institute of Rheumatology, Moscow.
Slovak Republic: F. Makai, J. Vojtassak, Clinic of
Orthopaedy, Bratislava.
Slovenia: A. Kocijancic, Klinicni Center Ljubljana,
Ljubljana.
South Africa: F. Hough, Tygerberg Hospital, Tygerberg.
Spain: M. Munoz-Torres, M. Quesada, F. EscobarJimenez, Hospital Clinico, Granada; J. Ferreiro, N.
Gomez, J. Ibanex, L. Corral, Clinica Povisa, Pontevedra;
A. Rapado, M. Diaz-Curiel, C. Turbi, Fundacion Jimenez
Diaz, Madrid; A. garcia-Vadillo, S. Castaneda, Hospital
la Princesa, Madrid; R. Perez-Cano, M. Vazquez, R.
Moruno, Hospital Clinico, Seville; C. Lozano, J. Jarreno,
Hospital Universitario San Carlos, Madrid; F. Hawkins,
E. Jodar, G. Martinez, Hospital Universitario 12 de
Octubre, Madrid; A. Torrijos, J. Gijon, Hospital La Paz,
Madrid; A. Diez-Perez, M. Martinex, X. Nogues,
Hospital del Mar, Barcelona; D. Roig-Escofet, M.
468
Romera, L. Mateo, A. Rozadilla, D. Roig-Villaseca,
Hospital Princeps D’Espanya, Barcelona; J. CalvoCatala, Hospital General Univeritario, Valencia; J.
Cannata, C. Gomez-Alonso, Hospital Central de Asturias, Oviedo; M. Sosa, R. de Castro, Facultad de Ciencias
Medicas, Las Palmas.
Sweden: G. Kallner, Medicinkliniken Sodersjukhuset,
Stockholm; E. Lette, Rontgenavd Sophiahemmet, Stockholm; D. Mellstrom, M. Stenstrom, Osteoporosmottagningen, Goteborg; M. Saaf, Karolinska sjukhuset,
Stockholm; G. Toss, Osteoporosenheten Universitetssjukhuset, Linkoping; B. Nyhall-Wahlin, Reumatologkliniken, Falun; E. Almqvist, Nova Medical Skarborg AB,
Skovde; I. Lager, Centralsjukhuset, Kristianstad; J.
Nordenstrom, L. Hellstrom, Huddinge sjukhus, Huddinge; S. Ljunghall, A. Schnell-Landstrom, Akademiska,
sjukhuset, Uppsala; O. Johnell, Malmö Allmanna
Sjukhus, Malmö.
Switzerland: M. Kraenzlin, Endokrinologische Abteilung, Kantonsspital, Basel; P. Jaeger, K. Lippuner,
Medizinische Universitätspoliklinik Inselspital, Berne;
R. Krapf, Med Klinik B, Kantonsspital, St Gallen.
Turkey: G. Dilsen, D. Singel, Istanbul University,
Istanbul; V. Sepici, J. Tan, Gazi University, Ankara.
United Kingdom: T. Price, T. Sheeran, A. Shubana, A.
Hassell, Cannock Chase Community Hospital, Cannock;
I. Fogelman, M. Jasani, G. Blake, Guy’s Hospital,
London; M. Davie, I. Chantler, R. Jones, A. Hunt,
Orthopaedic Hospital, Oswestry; G. Crawford, Community Pharmacology Services Ltd, Clydebank; K. Rajan,
East Glamorgan General Hospital, nr Pontypridd; T.
Wilkin, Freedom Fields Hospital, Plymouth, Devon; C.
Cooper, G. Pearson, Southampton General Hospital,
Southampton; I. Smith, J. Fraser, Wrightington Hospital,
Appley Bridge; P. Ryan, Medway Hospital, Gillingham;
P. Paciorek, BUPA St Saviour’s Hospital, Hythe.
Central Laboratory: Medical Research Laboratories,
Highland Heights, Kentucky, USA: P. Steiner, E. A.
Stein.
Central Quality Assurance Site for Bone Densitometry:
Medical Data Management, a division of Hologic, Inc.,
Waltham, Massachusetts, USA: K. Kastango, R. Rupich,
E. Yapchian.
Clinical Study Design: Merck & Co., Inc., Whitehouse
Station, New Jersey, USA: A. Till, current affiliation:
Generic Pharmaceutical Industry Association, Washington, DC.
Medical Program Coordinator: Merck & Co., Inc., West
Point, Pennsylvania, USA: E. Ricerca.
Medical Writing Assistance: Elizabeth V. Hillyer.
Acknowledgement. This study was supported by funding from Merck
& Co., Inc., Whitehouse Station, New Jersey, USA.
H. A. P. Pols et al.
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Received for publication 4 June 1998
Accepted in revised form 7 October 1998