Ten Years’ Experience With Alendronate for Osteoporosis in Postmenopausal Women

TLDR: The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period, and safety data did not suggest that prolonged treatment resulted in any loss of benefit.

Abstract: This multinational randomized double-blind trial, the Alendronate Phase III Osteoporosis Treatment Study, examined the results of alendronate therapy in postmenopausal women with osteoporosis who now have been followed for 10 years. A total of 227 women completed all phases of the study. Those participating were assigned to receive 5 or 10 mg of alendronate orally or placebo each day. The primary end point was the change in bone mineral density (BMD) in the lumbar spine. BMD also was measured at the femoral neck, trochanter, total proximal femur, forearm region, and the total body. From 17% to 31% of women in the various treatment groups had preexisting vertebral fractures. BMD continued to increase in the later years of the study in women given 5 or 10 mg of alendronate daily. The mean cumulative increase after 10 years in women taking 10 mg daily was 13.7%. Markers of bone remodeling (urinary N-telopeptides of type I collagen, bone-specific alkaline phosphatase) decreased, and this effect continued through 10 years of treatment. These markers increased within a year after alendronate was discontinued, although mean levels remained below baseline. There were no significant group differences in new vertebral fractures. The 3 groups also had similar safety profiles in the last 3 years of the study. No deaths were ascribed to alendronate therapy. Alendronate therapy continued to be effective over 10 years in these postmenopausal women, as estimated by both BMD measurements and effects on bone remodeling. The antifracture effect of alendronate did not appear to decrease over time.

Figures

Table 2. Mean Percent Change in Bone Mineral Density at Specified Intervals.*

Table 1. Base-Line Characteristics of Women Enrolled in the Third Extension of the Study and of All Participants in the Original Study.*

Figure 3 (facing page). Annualized Rate of Height Loss (Panel A) and Rate of Nonvertebral Fractures (Panel B) during Two Treatment Periods.

Table 3. Adverse Events Reported during Years 8 through 10.*

Full text

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Ten Years’ Experience with Alendronate for
Osteoporosis in Postmenopausal Women
Henry G. Bone
Michigan Bone and Mineral Clinic
David Hosking
Noingham City Hospital
Jean-Pierre Devogelaer
Université Catholique de Louvain
See next page for additional authors
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n engl j med
350;12
www.nejm.org march
18, 2004
The
new england journal
of
medicine
1189
original article
Ten Years’ Experience with Alendronate
for Osteoporosis in Postmenopausal Women
Henry G. Bone, M.D., David Hosking, M.D., Jean-Pierre Devogelaer, M.D.,
Joseph R. Tucci, M.D., Ronald D. Emkey, M.D., Richard P. Tonino, M.D.,
Jose Adolfo Rodriguez-Portales, M.D., Robert W. Downs, M.D.,
Jayanti Gupta, Ph.D., Arthur C. Santora, M.D., Ph.D.,
and Uri A. Liberman, M.D., Ph.D.,
for the Alendronate Phase III Osteoporosis Treatment Study Group
From Michigan Bone and Mineral Clinic,
Detroit (H.G.B.); Medical Research Center,
Nottingham City Hospital, Nottingham,
United Kingdom (D.H.); Saint-Luc Uni-
versity Hospital, Université Catholique de
Louvain, Brussels, Belgium (J.-P.D.); De-
partment of Medicine, Roger Williams
General Hospital, Providence, R.I. (J.R.T.);
Radiant Research–Reading, Wyomissing,
Pa. (R.D.E.); Good Health Associates in
Adult Medicine, South Burlington, Vt.
(R.P.T.); Departamento de Endocrinologia,
Escuela de Medicina, Universidad Catoli-
ca de Chile, Santiago, Chile (J.A.R.-P.); Vir-
ginia Commonwealth University, Richmond
(R.W.D.); Merck Research Laboratories,
Rahway, N.J. (J.G., A.C.S.); and Felsenstein
Medical Research Center, Sackler Faculty of
Medicine, Tel Aviv University, Petah-Tikva,
Israel (U.A.L.). Address reprint requests to
Dr. Bone at the Michigan Bone and Mineral
Clinic, 22201 Moross Rd., Suite 260, De-
troit, MI 48236.
N Engl J Med 2004;350:1189-99.
Copyright © 2004 Massachusetts Medical Society.
background
Antiresorptive agents are widely used to treat osteoporosis. We report the results of a
multinational randomized, double-blind study, in which postmenopausal women with
osteoporosis were treated with alendronate for up to 10 years.
methods
The initial three-year phase of the study compared three daily doses of alendronate
with placebo. Women in the original placebo group received alendronate in years 4 and
5 and then were discharged. Women in the original active-treatment groups continued
to receive alendronate during the initial extension (years 4 and 5). In two further exten-
sions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of
alendronate daily continued on the same treatment. Women in the discontinuation
group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and
5, followed by five years of placebo. Randomized group assignments and blinding
were maintained throughout the 10 years. We report results for the 247 women who
participated in all four phases of the study.
results
Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone
mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0
to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4
percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 per-
cent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to
9.1 percent) as compared with base-line values; smaller gains occurred in the group giv-
en 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as
measured by bone density and biochemical markers of bone remodeling. Safety data,
including fractures and stature, did not suggest that prolonged treatment resulted in
any loss of benefit.
conclusions
The therapeutic effects of alendronate were sustained, and the drug was well tolerated
over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of
its effects.
abstract
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n engl j med
350;12
www.nejm.org march
18
,
2004
The
new england journal
of
medicine
1190
ostmenopausal osteoporosis is a
chronic, progressive disorder in which bone
resorption exceeds formation, resulting in
decreased bone mass and deterioration of the mi-
croarchitecture, with consequent decreased bone
strength and increased susceptibility to fracture.
1,2
Antiresorptive agents are widely used to treat oste-
oporosis. The reduction in the risk of fracture dur-
ing antiresorptive treatment has been related to the
magnitude of changes in bone mineral density and
remodeling activity.
3-6
Alendronate, a potent inhib-
itor of bone resorption, has produced sustained re-
ductions in biochemical markers of bone remodel-
ing into the premenopausal range
7,8
and consistent
dose-related increases in bone mineral density in a
variety of populations, including elderly women.
7-14
These effects have been associated with a substan-
tially reduced risk of vertebral and nonvertebral
fractures.
3-5,15-20
Bone biopsy and histomorpho-
metric analysis have confirmed that normal bone
structure and mineralization are preserved and that
bone turnover is reduced but not completely sup-
pressed.
21
Mineralization is increased but remains
within the normal range.
22,23
The favorable effects
of alendronate on bone turnover, mass, and strength
have been confirmed in animal models.
24-26
In a pair of identical three-year randomized, pla-
cebo-controlled trials, alendronate increased bone
mineral density, decreased bone turnover, and re-
duced the risk of vertebral fracture among women
with osteoporosis.
7,8,20
To investigate the effects of
prolonged alendronate therapy as well as its discon-
tinuation, these trials were extended for a total of
10 years. Results for the first seven years have been
described.
27,28
In this article we report the results
through the final 3-year extension of the study, in-
cluding 5 years of observation after the discontinu-
ation of alendronate, and the cumulative, 10-year ex-
perience with alendronate.
study design
Two identical, concurrent multicenter, double-
blind, randomized, placebo-controlled phase 3
studies,
7,8,20
designed to permit pooling of results,
enrolled a total of 994 postmenopausal women with
osteoporosis that had been diagnosed on the ba-
sis of the bone mineral density of the lumbar
spine.
7,8,20,27
Initially, women were randomly assigned to re-
ceive 5, 10, or 20 mg of oral alendronate (Fosamax,
Merck) or placebo daily. Figure 1 shows the treat-
ment assignments for the original study and the ex-
tensions. Women in the placebo group were given
open-label alendronate for years 4 and 5 and then
discharged from the study. The original 5-mg and
10-mg alendronate groups continued to receive the
same doses in all three extensions of the study
(years 4 and 5, 6 and 7, and 8 through 10). Those in
the original 20-mg group received 5 mg for years
3 through 5 and placebo for years 6 through 10 (the
discontinuation group). Their cumulative exposure
to alendronate was similar to the exposure in the
10-mg group after 5 years and to that in the 5-mg
group after 10 years. Investigators and the women
were aware that all long-term participants had re-
ceived alendronate for at least five years and that the
discontinuation group had been switched to place-
bo, but all remained unaware of each woman’s cur-
rent treatment.
The women were instructed to take the study
medication daily, consistent with the instructions in
the product insert. They received 500 mg of calcium
daily. Vitamin D supplements were permitted but
not required.
Twenty-nine of the original 37 centers carried out
all three extension protocols, 17 within the United
States and 12 in other countries. These sites contrib-
uted 804 of the original 994 study participants. Of
the 482 women originally assigned to alendronate at
those sites, 247 (51.0 percent) participated in all
three extensions of the study. Protocols and exten-
sions were approved by institutional review boards.
Each woman gave written informed consent for the
study and each extension.
measurements
Efficacy End Points
The primary end point was the change in bone min-
eral density at the lumbar spine. Secondary end
points were changes in bone mineral density at the
femoral neck, trochanter, total proximal femur (“to-
tal hip”), total body, and forearm regions; changes
in the levels of urinary N-telopeptides of type I col-
lagen, a biochemical marker of bone resorption;
and changes in the levels of serum bone-specific al-
kaline phosphatase and total serum alkaline phos-
phatase, indicators of the rates of bone formation.
Bone mineral density was measured yearly by dual-
energy x-ray absorptiometry (Hologic, Lunar, and
Norland) and interpreted centrally by a quality-
assurance center (Hologic MDM/Synarc) in a blind-
ed fashion.
20,27
Biochemical markers were mea-
p
methods
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n engl j med
350;12
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18, 2004
alendronate for osteoporosis in postmenopausal women
1191
Figure 1. Treatment Assignments in the Original Three-Year Study and Its Extensions.
Of the original 994 women, 804 underwent initial randomization at sites that participated in the third extension of the
study. Overall, 51 percent of the women in the original three alendronate groups at those sites participated in the third
extension of the study. The numbers of women participating at those sites in the original study and the first and second
extensions are shown in parentheses.
994 (804)
Underwent randomization
3-Year Study
1st Extension, Years 4–5
2nd Extension, Years 6–7
3rd Extension, Years 8–10
86 (54.4% of 158)
Assigned to 10 mg
of alendronate
122 (105)
Assigned to 10 mg
of alendronate
196 (158)
Assigned to 10 mg
of alendronate
Ineligible for
further study
397 (322)
Assigned to
placebo
288 (232)
Assigned to 10 mg
of alendronate
151 (120)
Assigned to 10 mg
of alendronate
78 (47.6% of 164)
Assigned to 5 mg
of alendronate
113 (92)
Assigned to 5 mg
of alendronate
202 (164)
Assigned to 5 mg
of alendronate
145 (112)
Assigned to 5 mg
of alendronate
83 (51.9% of 160)
Assigned to placebo
115 (97)
Assigned to placebo
199 (160)
Assigned to 20 mg of
alendronate for yr 1–2
and 5 mg for yr 3
143 (114)
Assigned to 5 mg
of alendronate
* Plus–minus values are means ±SD. The discontinuation group was treated with 20 mg of alendronate per day for two
years and then 5 mg daily for three years, followed by placebo for five years. The 10-mg group was treated with 10 mg daily
for 10 years, and the 5-mg group was treated with 5 mg daily for 10 years. The body-mass index is the weight in kilograms
divided by the square of the height in meters. BCE denotes bone collagen equivalents, and NA not available.
† The mean base-line T score for the bone mineral density at the lumbar spine was ¡3.1. The entry criterion for bone min-
eral density was 0.80 g per square centimeter or less as measured by a Hologic or Norland densitometer and 0.92 g per
square centimeter or less as measured by a Lunar densitometer.
Table 1. Base-Line Characteristics of Women Enrolled in the Third Extension of the Study and of All Participants
in the Original Study.*
Characteristic
Discontinuation
Group
(N=83)
5-mg Alendronate
Group
(N=78)
10-mg Alendronate
Group
(N=86)
All Original
Participants
(N=994)
Age (yr) 63±6.2 64±7.2 63±6.0 63±7.0
Years since menopause 16±7.6 16±7.7 15±7.7 16±8.2
Body-mass index 25±3.5 24±3.6 24±2.9 24±3.5
Estimated calcium intake (mg/day) 704±459 838±516 747±563 738±539
Existing vertebral fractures (%) 27.2 30.8 17.5 20.6
Bone mineral density at lumbar spine
(g/cm
2
)†
Hologic or Norland densitometer
Lunar densitometer
0.71±0.1
0.81±0.1
0.70±0.1
0.80±0.1
0.70±0.1
0.82±0.1
0.71±0.1
0.81±0.1
Urinary N-telopeptides of type I collagen
(nmol of BCE/mmol of creatinine)
71.8 67.1 66.6 NA
Bone-specific alkaline phosphatase (ng/ml) 18.4 16.3 17.8 NA
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