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Alendronate Increases Bone Mass and Reduces Bone Markers in Postmenopausal African-American Women

Medical University of South Carolina and Veterans Affairs Medical Center (N.H.B.), Charleston, South Carolina 29425; Department of Medicine (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Michigan Bone and Mineral Clinic (H.G.B.), Detroit, Michigan 48236; and Merck Research Laboratories (A.K., A.M., A.C.S.), Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Norman H. Bell, M.D., Department of Medicine, Bone, and Mineral Metabolism, Medical University of South Carolina, 114 Doughty Street, P.O. Box 250775, Charleston, South Carolina 29425.

Abstract

Previous studies indicated that aminobisphosphonate alendronate sodium, a potent inhibitor of bone resorption, increases bone mineral density (BMD) at the hip and spine, reduces markers of bone turnover, and reduces the risk of fractures in Caucasian postmenopausal women. The purpose of the present study was to investigate whether alendronate increases BMD and reduces markers of bone turnover in African-American postmenopausal women. In a multicenter, randomized, double-blind, placebo-controlled study, 65 African-American women, aged 45 to 88 yr, were randomly assigned to either placebo (n = 33) or alendronate 10 mg daily (n = 32) for 2 yr. Mean BMD T scores of the lumbar spine at baseline were -3.18 in the placebo-treated group and -3.09 in the alendronate-treated group. All women took 500 mg elemental calcium daily in the form of calcium carbonate and 500 IU vitamin D. Alendronate significantly increased BMD and reduced markers of bone formation and resorption, compared with placebo. At 2 yr, mean changes ± SE in BMD were 6.5% ± 0.7% for the lumbar spine (P < 0.001), 4.5% ± 1.0% for the femoral neck (P < 0.001), 6.4% ± 0.6% for the femoral trochanter (P < 0.001), 4.1% ± 0.7% for the total hip (P < 0.001), 0.7% ± 0.5% for the one third forearm (NS), and 2.0% ± 0.4% for the total body (P < 0.001) in women treated with alendronate, compared with 0.9% ± 0.6% (NS), 0.5% ± 1.1% (NS), -0.2 ± 0.8 (NS), -1.1 ± 0.7% (NS), -0.8% ± 0.6% (NS), and -1.2% ± 0.6% (P < 0.05) for the lumbar spine, femoral neck, trochanter, total hip, one third forearm, and total body, respectively, in women treated with placebo. At 2 yr, mean serum bone-specific alkaline phosphatase had declined by 46.3% with alendronate (P < 0.001) and 13.6% with placebo (P < 0.01), and mean urinary N-telopeptide of type I collagen/creatinine ratio had declined by 70.5% with alendronate (P < 0.001) and 6.7% with placebo (NS). The incidence of adverse experiences was not different between the two groups. We conclude that in postmenopausal African-American women with osteoporosis, alendronate, 10 mg daily for 2 yr, increases BMD at the lumbar spine, hip, and total body and reduces markers of bone remodeling and is well tolerated.

ALENDRONATE IS A potent inhibitor of osteoclast- mediated bone resorption. The drug does not alter normal histology of skeletal tissue (1, 2, 3). In a primate animal model of estrogen deficiency, the drug was shown to increase bone strength in association with the increase in bone mass and fall in bone turnover (4). In previous clinical studies, alendronate was shown to increase bone mineral density (BMD), diminish skeletal remodeling, and reduce the incidence of fractures in postmenopausal Caucasian women (1, 3, 5, 6, 7, 8, 9, 10, 11). Alendronate rapidly reduces bone resorption as indicated by decreases in urinary N-telopeptide of type I collagen (NTx) at 3 months (1). This is followed by effects on bone formation as indicated by decreases in markers of bone formation, osteocalcin, and bone alkaline phosphatase (BSAP) at 3–6 months (1). Alendronate is well tolerated (1, 3, 5, 6, 7, 8, 9, 10, 11).

BMD is higher and the incidence of fractures including those of the hip is lower in African-American than in Caucasian postmenopausal women (12, 13, 14, 15, 16, 17). Nevertheless, many elderly African-Americans experience fractures, as do elderly Caucasians. When African-American women sustain a hip fracture, hospitalization is longer and mortality is higher, and they are more likely to be nonambulatory at the time of discharge (18, 19). Thus, treatment and prevention of osteoporosis is of major importance in African-American women. The present study was carried out to determine the safety and tolerability of alendronate and the effects of the drug on BMD and skeletal remodeling in postmenopausal African-American women with osteoporosis.

Subjects and Methods

Subjects

Sixty-five African-American postmenopausal women for this trial were recruited by advertisements and medical announcements. Inclusion criteria for this trial were age 45–88 yr, otherwise healthy, and a BMD 0.86 g/cm² or less (T score range -1.75 or less) at the lumbar spine as measured by model QDR 1000, QDR 1000W, or QDR 2000 bone densitometers (Hologic, Inc., Waltham, MA). Women with any disease or drug therapy potentially affecting bone metabolism or who had had more than one fracture of a lumbar spine vertebra were excluded. Other exclusion criteria included abnormal renal function or a history of cancer or major upper gastrointestinal mucosal erosive disease.

Study design

This multicenter, randomized, prospective, double-blind, placebo-controlled, parallel group, 2-yr study was conducted at eight institutions that were geographically distributed across the United States. The treatment protocol was approved by the investigational review board of each center, and written informed consent was provided by each study participant.

Patients were randomly assigned to receive either placebo or alendronate 10 mg daily for 2 yr. After a 2-wk run-in period in which placebo and calcium carbonate 500 mg plus vitamin D 250 IU/d were administered, women were instructed to take alendronate (Merck Research Laboratories, West Point, PA) or placebo orally once daily in the morning with a glass of water at least 30 min before consumption of any food, drink, or other medication and to remain in the upright position for at least 30 min after ingestion of the study medication. They were instructed to take 500 mg elemental calcium and 500 IU vitamin D (two OsCal 250 mg plus 250 IU vitamin D tablets, SmithKline Beecham, Pittsburgh, PA) orally at least 4 h after the study medication. The women were evaluated at 3-month intervals for the duration of the 2-yr study. Patient compliance was evaluated by pill counts and self-reporting of missing doses.

Bone mass measurements

BMD measurements were performed by dual-energy x-ray absorptiometry with QDR-1000, QDR-1000W, or QDR-2000 densitometers (Hologic, Inc.) as previously described (1). Measurements were obtained at the posteroanterior lumbar spine (L1-L4), and proximal femur (total hip, trochanter, and femoral neck) at baseline before administration of treatment and at 3, 6, 9, 12, 18, and 24 months. Measurements of the one third distal forearm, including radius and ulna, and total body were obtained at baseline and at 12, 18, and 24 months. Internal dual-energy x-ray absorptiometry calibration was maintained at each center, and cross-calibration among the centers was carried out with spine and linearity phantoms (Hologic, Inc.). All scans were monitored by a quality assurance center (Hologic, Inc. MDM).

Radiographic assessment

Lateral roentgenograms of the thoracic and lumbar spine were obtained at baseline and again on completion of treatment at 2 yr. They were evaluated for the presence or absence of prevalent or incident fractures, defined as a 20% or greater decrease in height of a vertebral body or a 4-mm decrease in vertebral height (Osteoporosis Research Group, University of California, San Francisco, California). Films were read by an experienced radiologist.

Biochemical analyses

Routine serum hematologic and chemistry values and urine chemistry values were measured by automated analysis at baseline and at 3, 6, 12, 18, and 24 months. Serum 25-hydroxyvitamin D was measured at baseline and serum intact PTH and 1,25-dihydroxyvitamin D were measured at baseline, 3, 6, 9 12, 18, and 24 months. Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and intact PTH were measured by RIA. Bone biochemistry measurements included BSAP and NTx. The Tandem-R Ostase immunoradiometric assay (Hybritech, San Diego, CA) was used to measure BSAP, and the Osteomark ELISA (Ostex International, Inc., Seattle, WA) was used to measure urinary NTx. The normal range for the BSAP assay is 2.9–14.5 ng/ml. The normal range for the urinary NTx assay is 5–65 nmol bone collagen equivalents/mmol creatinine.

Adverse experiences

Patients were questioned about any intercurrent health problems at each visit, and adverse experiences were noted by the physician who made a judgment as to whether the event was causally related to the study drug.

Statistical analysis

The primary efficacy end point was the difference between the placebo- and alendronate-treated groups in the percent change in lumbar spine BMD from baseline at 24 months. Secondary efficacy end points were the percent changes in total hip, trochanter, and total-body BMD and biochemical markers of bone turnover based on percent change from baseline to month 24. Intention to treat was the primary analysis approach for the BMD parameters. In this approach, if month 24 data were unavailable, the last postrandomization measurement was carried forward. However, patients were excluded from the intention-to-treat analysis if BMD data were not available for the baseline and for at least one additional visit after initiation of treatment. For analysis of biochemical markers, the log-transformed fraction of the baseline value at month 24 was used. No data were carried forward from one time point to another, and data from the patients who violated the protocol were excluded from the primary biochemical marker analysis. Pair-wise comparisons were made with ANOVA technique with treatment, center, and treatment-by-center interaction as factors. The interaction term was dropped from the model because it was insignificant (P > 0.1). Fisher’s exact test was used to compare treatment groups for proportion of patients outside the predefined limits of change.

Results

Baseline characteristics

The baseline characteristics of the 65 patients are shown in Table 1. The two groups were similar at baseline with regard to age, years since menopause, height, weight, BMD, and T scores at different sites and biochemical measurements. Baseline serum 25-hydroxyvitamin D was in the lower range of normal in both groups. Lumbar spine BMD for the subjects was about 1.75 SD below the normal young adult reference mean for African-American women and mean T scores were less than -3.0.

Sixty-five women were enrolled at eight participating centers, and 45 of them completed the 2-yr study, 22 (67%) in the placebo-treated group and 23 (72%) in the alendronate-treated group. Intent-to-treat analysis included 64 patients.

BMD

As shown in Fig. 1, there were progressive increases in BMD of the lumbar spine, total hip, femoral neck, and trochanter during the first year with stabilization during the second year in the alendronate-treated patients. Significant increases in BMD occurred at the lumbar spine, total hip, femoral neck, trochanter, and total-body BMD in patients treated with alendronate for 2 yr (Table 2). In contrast, either a nonsignificant increase or decrease in BMD occurred at these sites, except for total-body BMD in which a decrease was significant in patients given placebo. Alendronate increased BMD of the forearm, but the increase was not statistically significant. However, the difference in changes of forearm BMD between alendronate and placebo at 2 yr was significant (P = 0.027) as were the differences in BMD at all other sites.

View larger version (24K): [in this window] [in a new window]   Figure 1. Effects of alendronate on BMD in African-American postmenopausal women.

Urinary NTx fell in response to alendronate. Reduction in urinary NTx was apparent at 3 months and remained reduced for the remainder of the treatment period (Fig. 2). Urinary NTx remained at baseline values in the placebo-treated group for the entire 2-yr period. Serum BSAP decreased in both groups, but the decreases were significantly greater in the alendronate-treated group. The nadir for the decrease of serum BSAP in the alendronate-treated group was 12 months, whereas the nadir for urinary NTx was reached as soon as 3 months after therapy was begun. At the end of 2 yr, there were significant decreases in serum BSAP and urinary NTx in the alendronate-treated group (Table 3). Modest decreases in serum BSAP and urinary NTx also occurred in the placebo-treated group, but the changes were significantly greater in the alendronate-treated group (P < 0.001). Serum PTH and 1,25-dihydroxyvitamin D did not change significantly in either group during treatment. At the end of 2 yr, values were not significantly different from baseline in either group (Table 3). There was no significant treatment-by-center interaction in any of the BMD or biochemical measurements, indicating that the response to treatment was consistent among centers.

View larger version (15K): [in this window] [in a new window]   Figure 2. Effects of alendronate on bone markers in African-American postmenopausal women.

The tolerability profile of alendronate was favorable, compared with placebo (Table 4). The incidence of severe adverse experiences was similar in the two groups. Two patients withdrew as a consequence of an adverse experience in the alendronate-treated group and one in the placebo-treated group. The incidence of gastrointestinal adverse experiences was not significantly different between the two groups. The incidence of clinical fractures was higher in the placebo than in the alendronate-treated group, but the sample size was very small and the difference was not statistically significant.

The present study demonstrated that alendronate, 10 mg daily for 2 yr, increases BMD at the lumbar spine, femoral neck, total hip, and total body in postmenopausal African-American women with low bone mass of the spine. These results are similar to those found previously in postmenopausal Caucasian women (1, 3, 5, 6, 7, 8, 9, 10, 11). Alendronate decreased the rate of skeletal remodeling as indicated by reductions in serum BSAP and urinary NTx. These changes were noted as early as 3 months after starting treatment and are consistent with the known effects of the drug to inhibit osteoclastic bone resorption (1, 2, 3, 4, 5) and to reduce markers of skeletal remodeling in postmenopausal Caucasian women (1, 3, 5, 6, 7). The decrease in serum BSAP in response to alendronate presumably indicated a decrease in bone formation that followed a decrease in bone resorption as reflected by the decrease in urinary NTx. A smaller decrease in serum BSAP occurred in the placebo-treated group and was not associated with a change in urinary NTx. Whether this resulted from treatment with vitamin D and calcium is not known. In contrast to a previous study in Caucasian postmenopausal women in whom serum PTH and 1,25-dihydroxyvitamin D increased in response to alendronate (1), these values did not change in African-American women. The reason for the different in response is not known. In two comparable studies in postmenopausal Caucasian women of similar age with low BMD of the lumbar spine, alendronate, 10 mg daily for 2 yr, produced mean increases in BMD of 6.0% and 7.2% at the lumbar spine, 4.0% and 5.3% at the total hip, and 1.3% and 2.5% at the total body (1, 7), increases that are similar to those found in the present study in postmenopausal African-American women. In the women given placebo, BMD declined nonsignificantly at the lumbar spine, femoral neck, trochanter, total hip, and one-third forearm and significantly at the total body. A significant decrease in total body BMD was found previously in Caucasian women given a placebo (6).

It is well established that BMD is higher and the incidence of fractures is lower in African-American than in Caucasian postmenopausal women (12, 13, 14, 15, 16, 17, 18, 19). The mechanism for higher BMD in African Americans is not known, but skeletal resistance to PTH has been proposed as a factor, based on the diminished response of markers of bone resorption to PTH in African-American, compared with Caucasian women (20). Two histomorphometric analyses of biopsies of the iliac crest showed that bone formation rate is reduced in African-American, compared with Caucasian men and women (21, 22). Because BMD is higher and bone remodeling is lower in patients with either hypothyroidism or hypoparathyroidism (23), it was proposed that the lower bone turnover rate in African Americans is contributory or responsible for the their higher BMD values. It should be emphasized in the present study that alendronate appeared to be as effective in African-American as in Caucasian postmenopausal women in increasing BMD and reducing bone turnover despite lower bone turnover rates in the African-American women.

The incidence of hip fractures is lower in African-American than in Caucasian women (16, 17). However, African-American women who experienced a hip fracture require longer hospitalizations and are more likely to be nonambulatory at the time of discharge. The mortality rate is higher after hip fracture in African-American women (18, 19). Therefore, reducing the risk of hip fracture is a key therapeutic goal in African-American women. Alendronate increases BMD and reduces the vertebral and nonvertebral fracture rate in Caucasian women (1, 2, 3, 5, 6, 7, 8, 9, 10, 11). Because BMD is a powerful predictor of fracture risk, the comparable increases in BMD in African-American women suggests that reduction in fracture risk applies to African-American as well as Caucasian women.

Serum 25-hydroxyvitamin D was at the low end of the normal range in the women in the present study. In African Americans values are known to be lower than those in Caucasians. This difference is attributed to increased skin pigment and reduction of dermal production of vitamin D₃ caused by absorption of UV light by melanin (14, 20, 23).

Finally, the extent of genetic admixture of Caucasian in the African Americans in the present study is unknown. However, previous studies of polymorphisms of globulin haplotypes in African Americans suggest that it might be as much as 30% (24).

Acknowledgments

Footnotes

The Protocol 063 African-American Osteoporosis Study Group consisted of: John Bilezikian, M.D., Joan Glusman, M.D. (College of Physicians and Surgeons, Columbia University, New York, NY); Thomas Zizic, M.D. (Good Samaritan Hospital, Baltimore, MD); Anthony L. Mulloy, D.O. (Medical College of Georgia, Augusta, GA); Norman H. Bell, M.D., Judith Shary (Medical University of South Carolina, Charleston, SC); Kaur Amarjot, Adele Maragoto, Arthur C. Santora, M.D. (Merck Research Laboratories, Rahway, NJ); Henry G. Bone III, M.D. (Michigan Bone and Mineral Clinic, Detroit, MI); Nancy Lane, M.D. (San Francisco General Hospital, San Francisco, CA); Robert S. Weinstein, M.D. (University of Arkansas for Medical Sciences, Little Rock, AR); Sylvia Levis, M.D., A. Sampson (University of Miami, Miami, FL); William Applegate, M.D. (University of Tennessee–Memphis, Memphis, TN).

Abbreviations: Abbreviations: BMD, Bone mineral density; BSAP, bone-specific alkaline phosphatase; NTx, N-telopeptide of type I collagen.

Received November 19, 2001.

Accepted March 6, 2002.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bell, N. H. Articles by Santora, A. C. Search for Related Content PubMed PubMed Citation Articles by Bell, N. H. Articles by Santora, A. C.