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Original Studies |
Center for Clinical and Basic Research (P.R.), Ballerup DK-2750, Denmark; San Diego Endocrine and Medical Clinic (S.R.W.), San Diego, California 92108; Catholic University of Chile (J.A.R.-P.), Santiago, Chile; Oregon Osteoporosis Center (M.R.M.), Portland, Oregon 97213; Hawaii Osteoporosis Center (R.D.W.), Honolulu, Hawaii 96814; The Princess Margaret Hospital (N.L.G.), Christchurch 8002, New Zealand; University of Sydney, Royal North Shore Hospital (P.S.), Sydney 2065, Australia; Guy’s Hospital (I.F.), London, United Kingdom SE1 9RT; Merck & Co., Inc. (D.K., A.J.Y., A.D.), Rahway, New Jersey 07065; and American University of Beirut Medical Center (G.E.-H.F.), Beirut, Lebanon
Address all correspondence to: Pernille Ravn, M.D., Center for Clinical and Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Alendronate is a bisphosphonate, which has recently been introduced into clinical practice for treatment of osteoporosis, and results from large studies have suggested 10 mg/day oral alendronate as the optimal dose. This dose causes increases of 5–9% in spine and hip bone mineral density (BMD) over 2–3 yr (2, 3, 4, 5) and reduces the risk of vertebral and hip fractures by up to 50% (2, 6) in women with low bone mass or osteoporosis.
In contrast to treatment of osteoporosis, the aim of osteoporosis prevention is not to markedly increase, but rather to stabilize BMD. A dose of 5 mg/day oral alendronate seems to be the most appropriate dose with such effect and is the recommended dose for osteoporosis prevention in countries where alendronate is approved for this indication (7, 8). The use of alendronate for osteoporosis prevention has increased the potential application in clinical settings considerably, and it becomes important to define optimal treatment regimens over the longer term.
This study investigates the effect on bone mass and bone markers of treatment with 5 mg alendronate for 5 yr in recently postmenopausal women with normal bone mass. In addition, the effect after withdrawal of 2 yr of treatment with 20 mg alendronate is studied.
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Subjects and Methods |
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The study recruited healthy women, aged 40–59 yr, who were 6–36 months past menopause at study entry. FSH levels had to be in the postmenopausal range (42–126 IU/L). Subjects with a spinal BMD more than 2 SD above or below the young normal mean value or a history of nontraumatic spine or hip fractures were excluded. Women with disorders of bone and mineral metabolism were also excluded, as were those with a history of major upper gastrointestinal disease within 1 yr of study entry (such as peptic ulcer, esophageal disease, or malabsorption). Other exclusion criteria included previous treatment with bisphosphonates or fluoride (>1 mg/day) or treatment with estrogen, progestin, calcitonin, glucocorticoids, anticonvulsant agents, phosphate-binding antacids, or excessive vitamin A or vitamin D. Women who regularly used (>4 times/week) any medication that had the potential to cause gastrointestinal irritation (such as aspirin), who smoked more than 20 cigarettes/day, who drank 2 or more alcohol beverages/day, or who had a body weight more than 15% below or 30% above the ideal (as defined by the Metropolitan Health Insurance Co.) were also excluded. The study was approved by the local ethics committees and institutional review boards. All participants gave informed written consent. About 80% of the participants reported themselves as Caucasian.
Design
The study was a 3-yr dose-ranging, randomized, double blind,
placebo-controlled trial, followed by a 2-yr open label extension.
Dose-response data for the initial 3 yr of the study were published
previously (7). Of the 447 women enrolled at the original baseline, 311
women completed the initial 3 yr, 274 consented to continue in the
extension, and 263 completed all 5 yr. The 11 dropouts during the
extension were equally distributed across treatment groups. Here we
report 5-yr data from groups using the dose of alendronate currently
approved for osteoporosis prevention (5 mg) (7, 8) or the group in
which alendronate treatment was withdrawn. Fifty-two women received 5
mg alendronate for 5 yr (group I), 56 received 3 yr of placebo followed
by 5 mg alendronate during the extension (group II), and 52 received 20
mg alendronate for 2 yr and placebo during the third year and were
observed off therapy during the extension (group III; Fig. 1
).
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BMD
BMD was measured at the spine (primary end point), hip, total body, and wrist every 6 months during the double blind phase and every 12 months during the extension by dual energy x-ray absorptiometry (DXA) with a QDR-1000, 1000/W, or 2000 (Hologic, Inc., Waltham, MA; n = 97) or a DPX or DPX-L (Lunar Corp., Madison, WI) densitometer (n = 60). Total body (n = 115) and wrist (n = 91) measurements were made at centers with densitometers capable of performing these measurements. One bone densitometry quality assurance center (Oregon Osteoporosis Center), which remained blinded to treatment allocation, was responsible for the quality control of all participant and phantom scans. Phantoms were scanned daily at each center, and factors to correct for machine calibration drift were applied as necessary.
Bone markers
Fasting urinary excretion of N-telopeptide cross-links of type 1 collagen (NTX; Osteomark, Ostex International, Inc., Seattle, WA) was measured at 0, 3, 6, and 12 months and every 12 months thereafter. Fasting urinary excretion of C-telopeptides of type I collagen (CL; Urine CrossLaps enzyme-linked immunosorbent assay, Osteometer A/S, Rødovre, Denmark) was measured at baseline and every 12 months thereafter. Both NTX and CL were corrected for creatinine excretion and used as estimates of bone resorption in patients with available archived baseline urine specimens (n = 105 for NTX; n = 91 for CL). NTX and CL were analyzed centrally by Medical Research Laboratories (Heighland Heights, KY).
Statistical analysis
All participants who had a valid 3 yr and either 4 or 5 yr BMD measurement were included in the analyses. Within the double blind phase (0–3 yr) and extension (4–5 yr), missing data at a planned observation time were estimated by carrying forward the most recently observed data value. However, no data were carried forward from the double blind phase to the extension. Baseline demographic data were compared by one-way ANOVA. The changes in end-point observations from 0–5 yr were evaluated with one-sample t tests to determine whether the mean percent change was significantly different from zero. A stepwise multiple variable regression analysis was used to compare 1) the cumulative 3-yr bone loss in group III (2–5 yr), with the 3-yr bone loss in group II (0–3 yr), and 2) the cumulative 2-yr gain in bone mass in group I (0–2 yr), with the gain in bone mass in group II (3–5 yr). The percent change in BMD was the outcome variable, treatment was the main covariate, and age, years postmenopause, body mass index, and baseline BMD were additional covariates of interest. Squared terms, to test for a curvilinear relationship between response and covariates, and interaction terms, to test for treatment-related differences in the trend response over time, were evaluated and deleted from the regression model if they were not significant. Two-sample t tests were used to compare treatment means, adjusted for effects caused by age, years postmenopause, and baseline BMD. The cumulative rates of bone loss or bone gain were compared between the groups using the least significant difference (LSD) interval method. An 84% confidence interval was computed for the least squares (adjusted) mean response for each group to provide an assessment of the variability and magnitude of the mean percent change in BMD. If the groups did not overlap in confidence intervals, then the groups were different using an approximate 5% LSD test, and this implied a difference of P < 0.05 for between-groups test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). There were no
statistically significant differences in the baseline characteristics
of the participants in the original cohort, the participants entering
the extension, and the participants not entering the extension (data
not shown).
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). Bone loss at the wrist was attenuated
relative to that in the placebo group, but BMD decreased 3.4–4.8%
over 5 yr at the various regions of the wrist (ultradistal, middistal,
and one third distal region; all P < 0.001
vs. baseline). The effect of treatment with 5 mg alendronate
at the spine and hip was most pronounced during the initial 1–2 yr.
During the extension, decreases in BMD of 1.2% at the spine, 2.0% at
the femoral neck (both P < 0.01 vs. 3 yr),
0.7% at the trochanter (P = NS vs. 3 yr),
and 0.8% at the total body were observed (P < 0.05
vs. 3 yr).
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). In
comparison, the cumulative 3-yr bone loss in group II during yr 0–3
was 2.3–6.3%. There were no significant differences in the cumulative
bone loss rates during the respective periods between the two groups at
any skeletal region after adjustment for age, years since menopause,
body mass index, and baseline BMD.
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).
Furthermore, by the end of yr 5, BMDs in groups I and III were
comparable at all skeletal sites except the wrist, where BMD was 2–3%
higher in group I compared with that in group III (P <
0.01).
After adjustment for age, years since menopause, body mass index, and
baseline BMD, there were no significant differences between the 2-yr
gain in BMD during yr 0–2 in group I and the 2-yr gain in BMD during
yr 3–5 in group II (Fig. 3). However, group II had 2–3% lower bone
mass by the end of yr 5 compared with group I (P <
0.001; Fig. 2).
NTX and CL decreased within the first 12 months after the start
of treatment with 5 or 20 mg alendronate to a level 70–80% below
baseline values (P < 0.001; Fig. 4). The suppression of bone markers
tended to be more pronounced during treatment with 20 mg alendronate
than during treatment with 5 mg alendronate. The suppression of the
markers in groups I and II was comparable during treatment with 5 mg
alendronate. Upon withdrawal of alendronate (20 mg) in group III, both
markers partly reversed toward baseline, but remained 40–60% below
baseline values by the end of yr 5 (P < 0.001 for both
markers). However, from 36–60 months the level of CL in group III was
comparable to that in group II from 0–24 months. No consistent
correlations were observed between baseline values of the bone markers
and change in BMD.
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Discussion |
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Upon withdrawal of 2 yr of treatment with 20 mg/day alendronate, bone loss resumed at a yearly rate of 0.5–2%, which was comparable to the bone loss observed in the group initially taking placebo. Both markers of bone resorption partly reversed after withdrawal of alendronate, but remained below baseline values by the end of 5 yr. Because of the lack of a placebo group during the extension, the small number of urine specimens, and a relatively wide range of test results, the possibility remains that the persistent suppression of the markers in this group was at least partly caused by artifacts. However, alendronate is expected to have some long term effect on bone turnover after treatment withdrawal. Alendronate buried within the mineralized matrix of bone (14) is pharmacologically inactive (15). However, as bone resorption resumes after treatment withdrawal, alendronate is exposed on the resorption surfaces. Furthermore, consistent findings of bone loss despite suppression of the bone turnover markers have been reported previously. During the first 3 yr of the present study, a bone loss of about 1–2% was observed in the group treated with 1 mg/day alendronate, although NTX was suppressed by 40% (7). This indicates that complete prevention of bone loss only occurs once bone turnover is suppressed to premenopausal levels.
The study indicated that bone loss resumes at a normal postmenopausal rate after withdrawal of alendronate treatment. The stepwise multiple variable regression analysis, where age and years post menopause were covariates of interest, was used to compare bone loss in the group withdrawn from alendronate and the group taking placebo. The analysis compensated at least partly for a difference between the groups of 2 yr past menopause. However, because of the lack of a placebo group during the extension, we cannot rule out that natural slowing of bone loss during the withdrawal period partly explained the normal rate of bone loss observed after withdrawal of alendronate.
Several studies have investigated the effect on bone mass and bone turnover after withdrawal of alendronate or other bisphosphonates, but mostly in elderly postmenopausal women with osteoporosis. The studies have reported a partial or complete reversal of bone turnover and stable spine and hip BMD after withdrawal of 0.5–2 yr of treatment with oral alendronate (5–40 mg) or pamidronate (150 mg/day) (4, 16, 17, 18, 19). The results thus indicate that in elderly postmenopausal women with osteoporosis, the bone mass gained during bisphosphonate treatment is largely sustained even several years after treatment withdrawal. The sustained effect on bone mass observed in these studies might, however, also be partly explained by the continuous administration of calcium supplementation after withdrawal of the bisphosphonate (20).
In contrast, the few studies that have addressed withdrawal of bisphosphonates in younger postmenopausal women with normal bone mass have shown normalization of bone turnover and resumption of bone loss at a normal postmenopausal rate shortly after withdrawal of the bisphosphonate (21, 22, 23). These results are consistent with our present findings and indicate that the underlying natural bone turnover and resulting bone loss are greater in more recently postmenopausal women (24), thus resulting in an earlier reversal of bone turnover and bone loss after withdrawal of the antiresorptive agent. The implications may be that alendronate is more effective in recently postmenopausal women when administered continuously compared with a discontinuous administration.
Importantly, the present study also revealed that a comparable effect on bone mass at the spine, hip, and total body could be achieved by applying a higher dose of alendronate (20 mg) for a shorter period (2 yr) followed by a period off therapy (3 yr). However, because bisphosphonates are known to cause gastrointestinal side-effects at higher doses, 20 mg/day alendronate for 2 yr might present long term compliance problems (3, 4, 7). Long term randomized trials, which include arms with continuous and discontinuous treatments with standard accepted doses of alendronate, are still needed to elucidate these questions further and optimize treatment strategies for long term prevention of bone loss in recently postmenopausal women. This is being studied in the ongoing Early Postmenopausal Intervention Cohort study of oral alendronate (8, 23).
The gain in BMD during the initial 2 yr was similar in participants allocated to 5 mg/day alendronate at the original baseline and in participants switched to this dose after 3 yr of placebo treatment. This suggested that the effect on bone mass was independent of previous bone loss and is consistent with reports of a similar effect on BMD of 5 mg/day alendronate in elderly women with osteoporosis (25). However, participants who received placebo during the initial 3 yr had 2–3% lower bone mass by the end of 5 yr relative to those treated with 5 mg/day alendronate during all 5 yr. This indicates that the sooner alendronate treatment is instituted after the menopause, the greater the amount of premenopausal bone mass preserved.
In conclusion, 20 mg/day alendronate for 2 yr followed by 3 yr off therapy prevented postmenopausal bone loss in women with normal bone mass. In comparison, a 60% cumulative dose of alendronate administered as continuous alendronate (5 mg/day) for 5 yr had a comparable effect on spine, hip, and total body BMD, but a significantly greater effect on BMD at the wrist. The bone loss, which resumed after withdrawal of alendronate (20 mg), was comparable to normal early postmenopausal bone loss.
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Footnotes |
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1 This work was supported by Merck Research Laboratories in the form
of research grants to the individual study sites. 
2 The Alendronate Osteoporosis Prevention Study Group is made
up of the following: Investigative Centers and Clinical Investigators:
Richard Bauer, M.D. (University of Texas Health Science Center, San
Antonio, TX);
Pernille Ravn, M.D., Nina Bjarnason, M.D., Marianne Bidstrup, M.D., Bjørg Clemmesen, M.D., and Claus Christiansen, M.D., Ph.D. (Center For Clinical and Basic Research, Ballerup, Denmark); Jan Dequeker, M.D. (Universitair Ziekenhuis, Pellenberg, Belgium); John Eisman, M.D. (Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, Australia); Phillip Sambrook, M.D. (University of Sydney, Royal North Shore Hospital, Sydney, Australia); Ignac Fogelman, M.D., and Paul Ryan, M.D. (Guy’s Hospital, London, United Kingdom); Ghada El-Hajj Fuleihan, M.D., M.P.H. (Brigham and Women’s Hospital, Boston, MA); Piet Geusens, M.D. (Limburg Universitair Centrum, Diepenbeek, Belgium); Nigel Gilchrist, M.B., Ch.B. (Princess Margaret Hospital, Christchurch, New Zealand); Majorie Luckey, M.D. (Mount Sinai Medical Center, New York, NY); Michael McClung, M.D., Ana Balske, M.D., Ph.D. (Oregon Osteoporosis Center, Portland, OR); Charles Menkes, M.D. (Service de Rhumatologie A, Hôpital Cochin, Paris, France); Jose Rodriguez-Portales, M.D. (Catholic University of Chile, Santiago, Chile); Stephan Goemaere, M.D., and Jean Marc Kaufman, M.D. (UZ Gent Department of Endocrinology, Gent, Belgium); Richard Wasnich, M.D. (Hawaii Osteoporosis Center, Honolulu, HI); Stuart Weiss, M.D. (San Diego Endocrine and Medical Clinic, San Diego, CA). Bone Density Quality Assurance Center: Michael R. McClung, M.D., and Leslie Roberts (Oregon Osteoporosis Center, Portland, OR). Merck Research Laboratories (Rahway, NJ): Clinical Research: Anastasia Daifotis, M.D., Daniela Espinosa, B.S., Celia Reda, B.S., and A. John Yates, M.D.; Clinical Biostatistics: David Krupa, M.S., Shailaja Suryawanshi, Ph.D.
Received July 27, 1999.
Revised November 9, 1999.
Revised December 20, 1999.
Accepted January 4, 2000.
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