Prevention of Bone Loss with Alendronate in Postmenopausal Women under 60 Years of Age
David Hosking, M.D., Clair E.D. Chilvers, D.Sc., Claus Christiansen, M.D., Pernille Ravn, M.D., Richard Wasnich, M.D., Philip Ross, Ph.D., Michael McClung, M.D., Ana Balske, M.D., Ph.D., Desmond Thompson, Ph.D., Marianne Daley, B.A., A. John Yates, M.D., for The Early Postmenopausal Intervention Cohort Study Group
Background Estrogen-replacement therapy prevents osteoporosisin postmenopausal women by inhibiting bone resorption, but thebalance between its long-term risks and benefits remains unclear.Whether other antiresorptive therapies can prevent osteoporosisin these women is also not clear.
Methods We studied the effect of 2.5 mg or 5 mg of alendronateper day or placebo on bone mineral density in 1174 postmenopausalwomen under 60 years of age. An additional 435 women who wereprepared to receive a combination of estrogen and progestinwere randomly assigned to one of the above treatments or open-labelestrogen–progestin. The main outcome measure was the changein bone mineral density of the lumbar spine, hip, distal forearm,and total body measured annually for two years by dual-energyx-ray absorptiometry.
Results The women who received placebo lost bone mineral densityat all measured sites, whereas the women treated with 5 mg ofalendronate daily had a mean (±SE) increase in bone mineraldensity of 3.5±0.2 percent at the lumbar spine, 1.9±0.1percent at the hip, and 0.7±0.1 percent for the totalbody (all P<0.001). Women treated with 2.5 mg of alendronatedaily had smaller increases in bone mineral density. Alendronatedid not increase bone mineral density of the forearm, but itslowed the loss. The responses to estrogen–progestin were1 to 2 percentage points greater than those to the 5-mg doseof alendronate. Alendronate was well tolerated, with a safetyprofile similar to that of placebo or estrogen–progestin.
Conclusions Alendronate prevents bone loss in postmenopausalwomen under 60 years of age to nearly the same extent as estrogen–progestin.
Osteoporosis is a common and important cause of morbidity andmortality among postmenopausal women.1,2,3 It arises as a consequenceof progressive loss of bone and results in an increased riskof fracture. The destruction of trabecular microarchitecture,which cannot be repaired by currently available therapies, contributesto this mechanical weakness4 and has been an impetus to thedevelopment of strategies to maintain both bone mass and mechanicalintegrity.
Estrogen-replacement therapy is an established treatment forthe prevention of osteoporosis in postmenopausal women.5,6,7,8,9It acts by inhibiting bone resorption. Some women, however,cannot tolerate the side effects of estrogen, such as withdrawalbleeding or breast tenderness, and others are reluctant to takeestrogen because of the possible risk of breast cancer.10,11,12
Bisphosphonates also inhibit bone resorption and increase bonemineral density in postmenopausal women with osteoporosis.13,14,15Alendronate is a potent amino bisphosphonate16,17 that increasesbone mass15,18 and reduces the incidence of vertebral and otherfractures15,19 in postmenopausal women with osteoporosis.
The present study was performed to determine whether alendronateprevents bone loss in postmenopausal women and to compare theefficacy, safety, and tolerability of alendronate with thoseof a combination of estrogen and progestin.
Methods
Study Subjects
We studied 1609 women (age, 45 to 59 years) at four study centers.To be eligible for the study they had to have been postmenopausalfor at least six months (as confirmed by a high serum follicle-stimulatinghormone concentration) and in good health, with no clinicalor laboratory evidence of systemic disease. The following wereexclusion criteria: abnormal renal function (serum creatinine,>1.5 mg per deciliter [130 µmol per liter]), a historyof cancer, peptic ulcer or esophageal disease requiring prescriptionmedication within the previous five years, previous treatmentwith a bisphosphonate or fluoride, regular therapy with a phosphate-bindingantacid, estrogen-replacement therapy within the previous threemonths, and therapy with any other drug that affects the skeleton.To ensure that few women who entered the study had osteoporosis,only 10 percent of the women enrolled at each center were allowedto have a lumbar-spine bone mineral density below 0.8 g persquare centimeter, as measured by dual-energy x-ray absorptiometry.The women were recruited by direct mailings, advertisementsin the media, or telephone. The protocol was approved by theethics committee or institutional review board at each center,and all the women gave written informed consent.
Treatment
There were two treatment strata. In the first, the women wererandomly assigned to receive placebo or 2.5 mg or 5 mg of alendronatedaily, with both the women and the investigator being unawareof treatment-group assignment, or open-label estrogen–progestin.Women who had undergone hysterectomy or for whom estrogen–progestinwas contraindicated (because of thromboembolic disease or afamily history of estrogen-dependent cancer) or unacceptablewere enrolled in the second stratum, which was identical tothe first except that it did not include estrogen–progestin.In the United States the estrogen and progestin were given asconjugated estrogens (Premarin, Wyeth–Ayerst, Philadelphia,0.625 mg daily), and medroxyprogesterone acetate (Provera, Upjohn,Kalamazoo, Mich., 5 mg daily), respectively. In Europe the estrogenand progestin were given in a cyclical regimen (Trisequens,Novo Nordisk, Copenhagen, Denmark) of 2 mg of micronized estradiolper day for 22 days, 1 mg of norethindrone acetate per day ondays 13 to 22, and 1 mg of estradiol per day on days 23 to 28.
Dietary calcium intake was estimated at base line and annuallyduring the study with a food-frequency questionnaire. Womenwith a calcium intake of less than 500 mg per day were advisedto increase their intake. Supplements were not provided, becauseof the limited evidence of benefit in women soon after menopause.
Measurements of Bone Mineral Density
The bone mineral density of the lumbar spine, hip, forearm,and total body was measured by dual-energy x-ray absorptiometry(model 2000, Hologic, Waltham, Mass.) twice at base line andafter one and two years of treatment. The percent change frombase line in the measurement of the anteroposterior lumbar spine(vertebrae L1 to L4) was the primary end point, and the changesin the hip (defined as the femoral neck plus trochanter andintertrochanteric area), lateral spine, forearm (measured atthe junction of the proximal two thirds and the distal one thirdof the radial shaft where the radius and ulna meet near thewrist), and total body were secondary end points. Hologic MedicalData Management Services was responsible for handling all aspectsof the quality assurance for bone-mineral-density measurements,including calibration of machines, training of technicians,assessment of machine performance, adequacy of the scans obtained,analysis performed at the various sites, and data managementwithout knowledge of treatment assignment. Positioning of thepatients during absorptiometry and data analysis were standardized,as were calibration of the machines and training of the technicians.
Assessment of Safety of the Treatment
The women were questioned about any symptoms at clinic visitsevery three months. Standard clinical evaluations and laboratoryanalyses, including hematologic, renal-function, and liver-functiontests, were performed every six months. Physical examinationswere performed at base line and yearly thereafter, as was mammographyin the women receiving estrogen–progestin. If present,gastrointestinal symptoms were evaluated further if appropriate.All unfavorable or unintended clinical effects, including fractures,and laboratory abnormalities were considered adverse effectsand were evaluated by the investigators with respect to severity,duration, seriousness, and relation to the study drug and outcome.
Statistical Analysis
The two-year data reported here are from two planned interimanalyses in this six-year study. The primary evaluation of theefficacy data according to the intention to treat included all1460 women in whom lumbar-spine bone mineral density was measuredat base line and at least once during treatment.
The effect of treatment on bone mineral density was assessedby analysis of variance and included interaction terms for treatment,center, stratum, treatment with center, and treatment with stratum.All statistical tests were two-sided. The interaction termswere removed if the P value was not significant (P>0.10)or the interaction was nonqualitative in nature (according toSimon's test).20 Because the estrogen–progestin regimensdiffered in the U.S. and European centers, the comparison withalendronate was evaluated separately for each group.
Results
The base-line characteristics of the women are shown in Table 1.Women in the first stratum (placebo, alendronate, or estrogen–progestin)had more recently become postmenopausal (mean, four years) thanthose in the second stratum (placebo or alendronate) (mean,seven years), probably reflecting their higher prevalence ofmenopausal symptoms and greater willingness to consider estrogen–progestintreatment. There were no significant differences between thetreatment groups at base line.
Table 2. Distribution of the Women among the Treatment Groups in Stratum 1 (Placebo, Alendronate, or Estrogen–Progestin) and Stratum 2 (Placebo or Alendronate) and Reasons for Discontinuation of Treatment before Two Years.
Lumbar-Spine Bone Mineral Density
The anteroposterior lumbar-spine bone mineral density decreasedsteadily in the placebo group (mean [±SE] change forall women given placebo, -1.8±0.2 percent), whereas itincreased significantly in both alendronate groups (both stratacombined) (P<0.001 for both doses) (Figure 1A). Most of thegain in lumbar-spine bone mineral density in the alendronategroups occurred during the first year (2.0±0.1 percentin the 2.5-mg group and 2.7±0.1 percent in the 5-mg group,P<0.001 for both doses), but there were also significantincreases during the second year (0.3±0.1 percentagepoint in the 2.5-mg group, P = 0.003, and 0.8±0.1 percentagepoint in the 5-mg group, P<0.001). At both times the increasesin the 5-mg group were greater (P<0.001) than those in the2.5-mg group. The total gain at two years was 3.5±0.2percent in the 5-mg group and 2.3±0.2 percent in the2.5-mg group. The proportion of women who lost more than 2 percentof bone mineral density at the lumbar spine was 46 percent inthe placebo group, 9 percent in the group given the 2.5-mg doseof alendronate, and 5 percent in the group given the 5-mg doseof alendronate (Figure 2).
Figure 1. Mean (±SE) Percent Change from Base Line in Lumbar-Spine Bone Mineral Density after One and Two Years of Treatment with Placebo, 2.5 mg or 5 mg of Alendronate, or Estrogen–Progestin in the Total Cohort (Panel A), the U.S. Cohort (Panel B), and the European Cohort (Panel C).
Results for the two strata were combined according to treatment.
Figure 2. Proportion of Women with a Loss of More Than 2 Percent, a Change of 2 Percent or Less, or a Gain of More Than 2 Percent in Bone Mineral Density of the Lumbar Spine and Hip after Two Years of Treatment with Placebo, 2.5 mg or 5 mg of Alendronate, or Estrogen–Progestin.
Results for the two strata were combined according to treatment.
In the first stratum, the response at two years to estrogen–progestinin the U.S. women (Figure 1B) was slightly greater than theresponse to the 5-mg dose of alendronate (4.0±0.3 vs.2.9±0.5 percent, P = 0.06), whereas the response to estrogen–progestinin the European cohort was significantly greater than that to5 mg of alendronate (5.1±0.5 vs. 3.3±0.5 percent,P = 0.008) (Figure 1C).
The changes in bone mineral density of the lateral spine attwo years were similar to those of the anteroposterior spine(data not shown).
Hip Bone Mineral Density
The changes in the bone mineral density of the hip and its subregions(femoral neck and trochanter) were qualitatively similar tothose at the lumbar spine, with the main increase occurringwithin the first year (Figure 3). At two years, for both stratacombined, the changes from base line in the hip, femoral neck,and trochanter were -1.4±0.1 percent, -1.6±0.2percent, and -0.9±0.2 percent (all P<0.001), respectively,in the placebo group and 1.9±0.1 percent, 1.3±0.2percent, and 3.0±0.1 percent (all P<0.001), respectively,in the group given the 5-mg dose of alendronate. The differencesbetween treatment groups were significant (P<0.001) at eachof these sites. The proportion of women who lost more than 2percent of bone mineral density at the hip was 40 percent inthe placebo group, 10 percent in the group given the 2.5-mgdose of alendronate, and 6 percent in the group given the 5-mgdose of alendronate (Figure 2).
Figure 3. Mean (±SE) Change from Base Line in the Bone Mineral Density of the Hip, Distal Forearm, and Total Body after One and Two Years of Treatment with Placebo, 2.5 mg or 5 mg of Alendronate, or Estrogen–Progestin.
Results for the two strata were combined according to treatment.
In the U.S. cohort, estrogen–progestin increased hip bonemineral density at two years by 1.8±0.3 percent, as comparedwith 1.3±0.3 percent in the group receiving 5 mg of alendronateper day (P = 0.21). In the European cohort, the respective increaseswere 3.2±0.3 percent and 1.6±0.3 percent (P<0.002).
Forearm Bone Mineral Density
Bone mineral density of the distal forearm at two years decreasedby 2.5±0.1 percent in the placebo group and 1.4±0.1percent in the group given the 5-mg dose of alendronate (P<0.001for both) (Figure 3). The change in the U.S. cohort was -0.3±0.2percent among those receiving estrogen–progestin, as comparedwith -1.7±0.3 percent among those receiving the 5-mgdose of alendronate (P<0.001), whereas in the European cohortthe respective changes were 0.5±0.2 percent and -1.1±0.4percent (P<0.001).
Total-Body Bone Mineral Density
After two years of treatment, total-body bone mineral densitydecreased in the placebo group (-1.8±0.1 percent, P<0.001),did not change significantly in the group receiving 2.5 mg ofalendronate daily, and increased 0.7±0.1 percent in thegroup given 5 mg of alendronate daily (P<0.001) (Figure 3).Estrogen–progestin induced significantly larger increasesin total-body bone mineral density than 5 mg of alendronatein the European group (2.6±0.2 vs. 0.6±0.3 percent,P<0.001), but not in the U.S. group (1.2±0.2 vs. 0.8±0.3percent, P = 0.29).
The proportion of women who lost more than 2 percent of total-bodybone mineral density was 42 percent in the placebo group, 19percent in the group given the 2.5-mg dose of alendronate, and9 percent in the group given the 5-mg dose of alendronate.
Overall, there were no strong correlations between base-linecharacteristics and the changes in bone mineral density at twoyears.
Adverse Effects
Both doses of alendronate were well tolerated, and their safetyprofile was similar to that of placebo (Table 3). There wereno significant differences in the incidence of serious clinicaleffects or laboratory abnormalities between the alendronate,estrogen–progestin, and placebo groups. The rates of drug-relatedadverse events were similar in the alendronate and placebo groups,but those attributed to estrogen–progestin cannot be directlycompared because this treatment was open label. There was nosignificant difference between groups in the proportion of womenwith any adverse effect when effects were analyzed accordingto body system, including the upper gastrointestinal tract (Table 3),and there was no significant trend with increasing dose.The numbers of drug-related withdrawals were similar in thealendronate and placebo groups and higher in the estrogen–progestingroup (Table 2), but the total withdrawal rates were similarfor each treatment because of a balancing effect of non–drug-relatedwithdrawals due to menopausal symptoms in the alendronate groups.
Table 3. Summary of Adverse Events among the Treatment Groups in Both Strata.
Sixty-one women had fractures during the study, none of whichwere considered to be drug-related: 14 (3 percent) in the placebogroup, 22 (4 percent) in the group receiving 2.5 mg of alendronateper day, 22 (4 percent) in the group receiving 5 mg of alendronateper day, and 3 (3 percent) in the estrogen–progestin group.All were traumatic nonvertebral fractures.
Discussion
We found that in postmenopausal women without osteoporosis,alendronate increases bone mineral density at most sites andthat a daily dose of 5 mg was more effective than a dose of2.5 mg. The increments in bone mineral density in the 5-mg groupapproached those in the estrogen–progestin group and weresimilar to those achieved with the same dose in two studiesof older women with osteoporosis.15,18 In the second study,10 mg of alendronate daily produced the greatest gains in bonemineral density,18 but our study was designed to identify thelowest dose that would maintain or increase bone density ina substantial majority of women rather than produce the maximalgain. In contrast to the results at most sites, forearm bonemineral density decreased in the alendronate-treated women,but not as much as in those given placebo. In a recent placebo-controlledstudy of alendronate, there was a 48 percent reduction in theincidence of forearm fractures in the context of a gain of about1 percent in forearm bone mineral density,19 suggesting thatincrements in bone mineral density may account only in partfor the antifracture efficacy of alendronate.
Estrogen–progestin prevented bone loss at all sites toan extent similar to that reported previously.7,21,22,23 Thegain in bone mineral density was 1 to 2 percentage points greaterthan that achieved with alendronate. Some women in both alendronategroups lost bone mass. This effect of alendronate has to beaccepted, since the aim of prevention is to achieve a moderateincrease in bone density on average or at least to prevent ongoingbone loss.
Since both the 5-mg dose of alendronate and estrogen–progestinprevent bone loss in postmenopausal women under the age of 60years, the choice of therapy for any woman may well be determinedby the safety and tolerability of the treatment. In view ofreports of esophageal ulceration with alendronate,24 upper gastrointestinalsymptoms were carefully monitored and, when present, were investigatedas clinically appropriate. We found, however, that the safetyand tolerability of a 5-mg dose of alendronate were similarto those of placebo. Caution should be used in interpretingthe safety and tolerability of open-label estrogen–progestin,because of the potential for investigator reporting bias. Theadverse effects of estrogen–progestin reported were typicalof known effects, such as withdrawal bleeding and breast tenderness,and as a consequence were more likely to be classified as drug-related.
Estrogen–progestin is recommended for women who want controlof menopausal symptoms and protection from osteoporosis. Theprobable benefit of estrogen with respect to coronary heartdisease25,26 may also attract women with risk factors for thiscondition. Among women who have not had a hysterectomy, however,these advantages may be offset by side effects from the additionof progestins or withdrawal bleeding.27 Fear of breast canceris also a disincentive to some women, although there is no consensuson the magnitude of the risk.11,12,28
In conclusion, alendronate is effective in preventing bone lossin postmenopausal women and therefore provides an alternativeto estrogen (with or without progestin) in women for whom thetherapeutic goal is to maintain bone mass and thus reduce therisk of future fractures.
Supported by a grant from Merck Research Laboratories.
We are indebted to Dr. Reynold Spector for his support and guidancein the initiation of this project.
* The other members of the Early Postmenopausal Intervention CohortStudy Group are listed in the Appendix.
Source Information
From the Division of Mineral Metabolism, City Hospital (D.H.), and the School of Community Health Sciences, University of Nottingham Medical School (C.E.D.C.), Nottingham, United Kingdom; the Center for Clinical and Basic Research, Ballerup, Denmark (C.C., P. Ravn); the Hawaii Osteoporosis Center, Honolulu (R.W., P. Ross); Oregon Osteoporosis Center, Providence Health System, Portland (M.M., A.B.); and Merck Research Laboratories, Rahway, N.J. (D.T., M.D., A.J.Y.).
Address reprint requests to Dr. Hosking at the Division of Mineral Metabolism, City Hospital, Hucknall Rd., Nottingham NG5 1PB, United Kingdom.
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Appendix
The following investigators also participated in the study:Hawaii Osteoporosis Center, Honolulu: D. Uyeda, L. Medina, J.Silva, J. Carlson, M. Chong, G. Gibb, S. Caindec-Ranchez, N.Iinuma, B. Choo; Oregon Osteoporosis Center, Portland: B. Love,P. Workman, N. Parkins, E. Stephens, E. Kingston, R. Mansfield,C. Kowalski; Bone and Mineral Unit, Nottingham City Hospitaland School of Community Health Sciences, Medical School, Nottingham,United Kingdom: A. Lyons, S. Patel, C. Coupland, D. Green, P.San, A. Worley, S. Cliffe, S. Cawte, N. Keating; Center forClinical and Basic Research, Ballerup, Denmark: B. Clemmesen,P. Alexandersen, L. Petersen, J. Jorgensen, I. Bergmann, L.Vilstrup Moller, G. Hansen, A. Pedersen, M. Jakobsen, K. Overgoard,K. Bjarnson, A. Mollgaard Jensen; Hologic, Medical Data ManagementDivision, Waltham, Mass.: P. Steiger, E. Yapchian, S. Steiger;Merck Research Laboratories, Rahway, N.J.;Hoddesdon, UnitedKingdom; and Copenhagen, Denmark: A. Maragoto, E. Weinberg,G. Cizza, C. Allen, M. Stephens, J. Butcher, S. Marquiss, J.Dollerup, R. Elkjaer, I. Bybaek.
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