Effect of alendronate on bone mineral density and ... - Springer Link

J Bone Miner Metab (2003) 21:421–427 DOI 10.1007/s00774-003-0438-2

© Springer-Verlag 2003

Effect of alendronate on bone mineral density and bone turnover in Thai postmenopausal osteoporosis La-or Chailurkit, Wallaya Jongjaroenprasert, Sasithorn Rungbunnapun, Boonsong Ongphiphadhanakul, Sunee Sae-tung, and Rajata Rajatanavin Department of Medicine, Ramathibodi Hospital, Mahidol University, Rama 6th Road, Bangkok, Thailand

Abstract Alendronate has recently been approved for the prevention and treatment of postmenopausal osteoporosis, and its efficacy has been demonstrated in many Western countries. Our present study was performed to evaluate the effect of alendronate on bone mineral density (BMD) and its tolerability in Thais. Eighty postmenopausal women with osteoporosis participated in this study. After giving informed consent, the subjects were randomly allocated either 10 mg alendronate or placebo in a double-blind fashion. All patients received a supplement of 500 mg elemental calcium daily. BMD at the lumbar spine, femoral neck, and distal forearm was measured at baseline and 6 and 12 months after treatment. Biochemical markers of bone resorption were determined at baseline and 6 months after treatment. Baseline characteristics were similar in both alendronate- and placebotreated groups. Ten subjects discontinued the study. Of 70 subjects, 32 received 10 mg alendronate daily and the remaining subjects received placebo. At 1 year, BMD in the alendronate-treated group had increased from baseline by 9.2%, 4.6%, and 3.1% at lumbar spine, femoral neck, and distal forearm, respectively. These percentages were greater than those in controls (4.1%, 0.6%, and 1.0%, respectively). Urinary N-terminal telopeptide (NTx)-I and serum Cterminal telopeptide (CTx)-I levels decreased in both groups after 6 months of treatment. However, more reduction was demonstrated in the alendronate-treated group (71.9% vs. 28.4%, P ⬍ 0.01, and 84.7% vs. 33.1%, P ⬍ 0.01, respectively). Compliance with treatment and drug tolerability were good in both alendronate and placebo groups. We concluded that treatment with alendronate 10 mg daily for Thai postmenopausal women with osteoporosis significantly increased BMD at all skeletal sites and reduced biochemical markers of bone resorption. It was well tolerated without any serious side effects.

Offprint requests to: L. Chailurkit Received: November 18, 2002 / Accepted: March 24, 2003

Key words alendronate · postmenopausal osteoporosis · bone mineral density · biochemical markers of bone resorption

Introduction Osteoporotic fractures lead to a marked reduction in quality of life and much health care expenditure. The incidence of osteoporotic fractures has been shown to rise exponentially with age [1,2]. Women, especially when postmenopausal, are likely to develop osteoporotic fractures much more frequently than men due to lower peak bone mass, accelerated bone loss after the menopause, and greater longevity. Currently, a number of antiresorptive agents have become the mainstay of prevention and treatment of postmenopausal osteoporosis. Hormone replacement therapy (HRT) is an antiresorptive agent that has been shown to maintain or increase bone mass in osteoporotic postmenopausal women [3–5]. However, overall health risks including cardiovascular disease, breast cancer, and thomboembolism exceed the benefit from use of HRT, as recently demonstrated by the Women’s Health Initiative Study [6]. Bisphosphonate is another choice of antiresorptive agents for treatment of osteoporosis with a good safety profile [7]. A potent aminobisphosphonate such as alendronate has been shown to prevent bone loss and to substantially increase bone mass by acting as a potent inhibitor of bone resorption [8,9]. Recent studies have demonstrated that alendronate is effective therapy for treatment of osteoporosis in postmenopausal women [10–14]. However, these findings were reported in Western countries, and response to treatment might differ among countries for reasons of bone geometry or genetic or ethnic differences. Therefore, the purpose of this study is to assess the effect of alendronate on bone mineral density (BMD) and biochemical markers of

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L. Chailurkit et al.: Efficacy of alendronate in Thai postmenopausal osteoporosis

bone turnover as well as its tolerability in Thai postmenopausal women with osteoporosis.

Material and methods Subjects Eighty healthy postmenopausal women less than 80 years of age were recruited from the metabolic bone clinic at Ramathibodi Hospital, Bangkok, Thailand. All had osteoporosis, defined as BMD of the lumbar spine (L2–L4) and/or femoral neck at least 2.5 standard deviations (SD) below the mean for young Thai adults. All subjects had experienced a spontaneous menopause. Women with metabolic bone disease other than postmenopausal osteoporosis, disturbed parathyroid or thyroid function, major gastrointestinal disease, uncontrolled hypertension, or any prior treatment with bisphosphonate within the preceding 6 months, with estrogen or calcitonin within the preceding 4 months, or with an anabolic steroid, glucocorticoid, were excluded. Eligible women were randomly assigned to receive 10 mg alendronate (Fosamax; Merck Sharp & Dohme) or matching placebo tablets once daily for 12 months. Subjects were instructed to take alendronate or the matching placebo orally with a glass of plain water (~200 ml) at least 30 min before the first food, beverage, or medication of the day each morning. They were also instructed to remain upright for at least 30 min after dosing and after the first food of the day. All subjects also received supplemental elemental calcium 500 mg/ day (as carbonate, two 250-mg capsules) with the evening meal. Compliance was monitored by tablet counts at each visit. This study protocol was approved by the Committee on Clinical Investigation at Ramathibodi Hospital. Written informed consent was obtained from every subject. Bone mineral density Measurements of BMD were made by dual-energy Xray absorptiometry (DXA) at the lumber spine (L2– L4), femoral neck, and distal forearm at baseline and then at 6 and 12 months after the initiation of therapy on a Lunar Expert XL (Lunar, Madison, WI, USA). Daily calibration and quality control were performed regularly according to the manufacturer’s instructions. In vivo coefficient of variation (CV) for the anteroposterior lumbar spine (L2–L4) and femoral neck was 1.2% and 1.6%, respectively.

Biochemical markers Twenty-four-hour urine and serum samples were obtained from all subjects at baseline and at 6 months after the start of treatment and stored at ⫺20°C until the measurements were made. All blood samples were collected between 7:30 a.m. and 9:00 a.m. after an overnight fast. To follow the effect of alendronate treatment on the rate of bone turnover, two markers of bone resorption, urinary N-terminal telopeptide (NTx-I) and serum C-terminal telopeptide (CTx-I) of type I collagen, were measured. Urinary NTx-I was analyzed by luminescence immunoassay using Vitros NTx assay on an automated Vitros Immunodiagnostic System analzer (Ortho-Clinical Diagnostics, Buckingham-shire, UK). The concentration of urinary NTx-I was expressed as the ratio to urinary creatinine. Serum CTx-I was determined by electrochemiluminescence immunoassay using β-CrossLaps on an automated Elecsys 1010 System analyzer (Mannheim, Germany). The within-assay CVs for urinary NTx-I (mean concentration, 13.7–58 nM/ mM creatinine) and serum CTx-I (mean concentration, 0.14–0.65 ng/ml) were 4.1%–8.5% and 3.4%–5.4%, and the between-assay CVs were 4.4%–9.5% and 4.1%– 5.2%, respectively. Statistical analysis Results are presented as the mean ⫾SD unless otherwise indicated. The changes of BMD or bone markers with time were expressed as the percentage of increase or decrease from baseline value. Normality of the results was assessed by the Kolmogorov–Smirnov test. A nonparametric method was used if the result was not normally distributed. Student’s unpaired t test was used to compare the baseline characteristics between the placebo and alendronate groups. Repeated-measures ANOVA with the Newman–Keul post hoc test was performed within groups to assess the different BMD between the baseline level and the absolute value of changes of BMD at 6 and 12 months after treatment. The Wilcoxon rank sum test was used to determine the significance of biochemical markers of bone resorption change from baseline. Comparisons of percent change from baseline between groups at specific times points used the Mann–Whitney U test. Associations between two parameters were determined by the Pearson correlation coefficient or Spearman’s rank correlation. Statistical significance was assigned at P ⬍ 0.05. All tests were two-tailed.


Results General characteristics Among 80 postmenopausal women randomized, 70 (87.5%) completed the study. Thirty-two women received 10 mg alendronate daily and the remaining women receive the placebo. The baseline characteristics according to their treatment are shown in Table 1. No overall significant difference was observed between the alendronate and placebo groups with regard to their age, body mass index, and years since menopause. The baseline lumbar spine, femoral neck, and distal forearm BMD, as well as the bone resorption markers urinary NTx-I and serum CTx-I, also did not differ between the two groups. Compliance of the alendronate and placebo groups was 96% and 97%, respectively.

BMD measurement BMD increased at each site during the first 6 months and progressively increased up to 1 year in those who received 10 mg alendronate daily (Table 2). However, distal forearm BMD did not show a significant increase when compared to baseline values. In the placebo group, who received calcium alone, significant increase

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in BMD occurred only at the lumbar spine at both 6 months and 1 year. Mean percent change in BMD relative to baseline after 6 and 12 months therapy is shown in Fig. 1. At the end of 1 year, treatment with alendronate significantly increased mean percent change from baseline of BMD at lumbar spine (9.2%) and femoral neck (4.6%) compared with placebo (4.1% and 0.6%, respectively; both P ⬍ 0.05). However, the percent increase from baseline in distal forearm BMD (3.1%) after 1 year of alendronate therapy was not significantly different from the placebo group (1.0%). Biochemical markers of bone turnover At 6 months, the mean absolute values of urinary NTxI and serum CTx-I decreased significantly compared to baseline values in both alendronate and placebo groups (see Table 2). However, the corresponding changes in the placebo group were less impressive. The mean percent changes from baseline in urinary NTx-I and serum CTx-I after 6 months of treatment decreased by 71.9% and 84.7% in the alendronate group and 28.4% and 33.1% in the placebo group, respectively (Fig. 2). A significant difference of the mean percent changes from baseline of urinary NTx-I and serum CTx-I between the alendronate and the placebo groups was also observed.

Table 1. Baseline characteristics of 70 postmenopausal women according to their treatment Alendronate, mean ⫾ SD (range)

Variable Number Age (years) Years since menopause Body mass indexa Lumbar spine BMD (g/cm2) Femoral neck BMD (g/cm2) Distal forearm BMD (g/cm2) Serum alkaline phosphatase (U/l) Urinary NTx-I (nM/mM Cr) Serum CTx-I (ng/ml)

62.2 12.6 22.3 0.80 0.72 0.63 71.6 40.6 0.38

32 ⫾ 6.4 (51–79) ⫾ 7.0 (1–29) ⫾ 2.9 (16.0–30.7) ⫾ 0.087 (0.56–1.01) ⫾ 0.106 (0.51–0.95) ⫾ 0.110 (0.42–0.85) ⫾ 21.9 (33–121) ⫾ 38.8 (2.8–187.9) ⫾ 0.24 (0.07–1.16)

Placebo, mean ⫾ SD (range) 61.8 ⫾ 12.8 ⫾ 22.4 ⫾ 0.79 ⫾ 0.68 ⫾ 0.62 ⫾ 69.4 ⫾ 45.2 ⫾ 0.38 ⫾

38 5.6 (49–75) 6.6 (2–28) 3.5 (14.4–31.7) 0.079 (0.56–0.88) 0.105 (0.45–0.88) 0.102 (0.34–0.82) 18.3 (42–124) 39.6 (5.5–180.3) 0.21 (0.06–1.06)

P ⬎0.05 ⬎0.05 ⬎0.05 ⬎0.05 ⬎0.05 ⬎0.05 ⬎0.05 ⬎0.05 ⬎0.05

BMD, bone mineral density; Cr, creatinine; NTx, N-terminal telopeptide; CTx, C-terminal telopeptide a Body mass index was calculated as weight in kilograms divided by the square of height in meters

Table 2. Mean values of BMD and biochemical markers of bone resorption at baseline and at 6 and 12 months after treatment Placebo 0 2

Lumbar spine BMD (g/cm ) Femoral neck BMD (g/cm2) Distal forearm BMD (g/cm2) Urinary NTx-I (nM/mM Cr) Serum CTx-I (ng/ml)

0.79 ⫾ 0.68 ⫾ 0.62 ⫾ 45.2 ⫾ 0.38 ⫾

6 0.08 0.10 0.10 39.6 0.21

Values are mean ⫾ SD * Significant difference from baseline value, P ⬍ 0.001

0.82 0.69 0.62 25.1 0.22

⫾ 0.09* ⫾ 0.10 ⫾ 0.10 ⫾ 28.1* ⫾ 0.11*

Alendronate 12 0.82 ⫾ 0.09* 0.69 ⫾ 0.11 0.62 ⫾ 0.10

0 0.80 0.72 0.63 40.6 0.38

⫾ ⫾ ⫾ ⫾ ⫾

6 0.09 0.11 0.11 38.8 0.24

0.85 0.74 0.64 8.89 0.05

⫾ 0.10* ⫾ 0.11* ⫾ 0.11 ⫾ 7.60* ⫾ 0.03*

12 0.87 ⫾ 0.11* 0.76 ⫾ 0.10* 0.65 ⫾ 0.11

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Fig. 2. Percent change from baseline in biochemical markers of bone resorption of postmenopausal osteoporosis receiving placebo (dotted line) or alendronate (solid line) for 6 months. Data are mean ⫾ SE. NTx, N-terminal telopeptide; CTx, Cterminal telopeptide. *P ⬍ 0.05 (alendronate vs. placebo)

Fig. 1. Percent change from baseline in bone mineral density (BMD) of postmenopausal osteoporosis patients receiving placebo (dotted line) or alendronate (solid line) for 1 year. Data are mean ⫾ SE. *P ⬍ 0.05 (alendronate vs. placebo)

Relationship between BMD and biochemical markers of bone turnover In 70 women with osteoporosis treated with alendronate 10 mg/day or placebo, both the baseline values and changes from baseline at 6 months of serum CTx-I correlated with the changes from baseline in BMD at 1 year only at the lumbar spine (r ⫽ 0.433 and

r ⫽ ⫺0.327; both P ⬍ 0.01) (Fig. 3). Neither baseline values nor the changes from baseline at 6 months in urinary NTx-I correlated with the changes from baseline in BMD at 1 year. Adverse effects Ten of 80 postmenopausal women discontinued participation in the study. Eight of 10 were in the adrendronate group. Two of them (5% of the women receiving alendronate) developed clinical adverse effects (abdominal pain and musculoskeletal pain, respectively). One woman died of myocardial infarction. Three women were uncooperative, and 2 women were lost to follow-up. The remaining 2 withdrawals were on placebo. One of them had asthma, which required glucocorticoid therapy, and the other was uncooperative.


Fig. 3. Relationship between the baseline values or percent change from baseline at 6 months of serum CTx and the percent change from baseline at 1 year of lumbar spine BMD

Discussion Alendronate was generally well tolerated in the study population with no serious clinical adverse effect. Daily treatment with 10 mg oral alendronate at 1 year was effective in increasing BMD at the spine and hip in Thai women with postmenopausal osteoporosis. These results were consistent with previous studies [15,16]. Significant improvements in bone density by the action of antiresorptive drugs are also reported to have an association with reduced incidence of fracture rate [17–19]. However, this was not the case in distal forearm BMD, where the increment was only slight. The slight change of forearm BMD with alendronate therapy was also consistent with many previous reports [15,18,20,21]. These results may imply that the less expensive portable BMD measurement devices, which are designed to quickly and simply assess peripheral skeletal sites such as the forearm and finger, might not be as effective as those that measure the central skeleton in monitoring the response to alendronate therapy. In addition, the

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magnitude of increment in BMD from baseline to alendronate therapy varied substantially according to the skeletal site, being greatest in lumbar spine, moderate in femoral neck, and lowest in distal forearm. The difference might be due to the different ratios of cancellous bone to cortical bone at each skeletal site. The lumbar spine has a higher proportion of cancellous bone than the femoral neck whereas the distal forearm is made up almost entirely of cortical bone [22,23]. In addition, the rate of turnover in cortical bone was much lower than in trabecular bone [24]. A low turnover site may limit the potential gain in bone mass, whereas a high turnover site may permit a larger gain in BMD. Therefore, the high turnover sites are likely to respond to antiresorptive therapy better than low turnover sites and should be used to assess therapeutic efficacy. Alendronate therapy also induces a reduction in bone resorption. Both urinary NTx-I and serum CTx-I levels showed a rapid and pronounced decrease after alendronate therapy. Similar results were reported previously [9,25], indicating that alendronate was a potent antiresorptive agent. In addition, the decrease in bone resorption was found within 6 months when changes in BMD were not yet seen. Therefore, the measurement of bone resorption markers might provide a clinically useful early screening of treatment effect on bone. Although both urinary NTx-I and serum CTx-I were suppressed during alendronate therapy, only serum CTx-I, both baseline value and percent change from baseline at 6 months, could predict change in spinal BMD at 1 year. However, not all studies have consistently found a relationship between change in a marker and change in BMD at different skeletal sites after antiresorptive therapies. Fink et al. previously showed that, among all biochemical parameters tested, serum CTx-I was the most effective biochemical index for monitoring and predicting the response to alendronate therapy [26]. In addition, they also found that change in serum CTx-I was the best predictor of gain in spinal BMD after 1 year, whereas urinary NTx-I was the second best predictor. In agreement with these data, our study also showed that both baseline and the short-term change in serum CTx-I correlated with the long-term change in lumbar spine BMD. However, neither baseline nor early change in urinary NTx-I could predict the long-term changes in any site of BMD. Braga de Castro Machado et al. observed the same association of urinary NTx-I as we did [27]. It seemed likely that the association between bone turnover and BMD changes was usually stronger with the more precise BMD measurement (spine vs. hip) and stronger with the most sensitive and specific bone markers. Other authors and we ourselves have recently shown that serum CTx-I had a higher specificity and sensitivity than other markers in assessing efficacy of antiresorptive therapy [28–30].

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Therefore, serum CTx-I measurement would be useful not in only monitoring treatment efficacy but also in predicting the spinal BMD response to alendronate treatment. In addition, the mean percent change from baseline of BMD as well as of biochemical markers of bone turnover in the alendronate group was significantly greater than in the placebo group. These data demonstrated that alendronate alone was effective in increasing BMD and decreasing bone turnover. Furthermore, calcium supplement alone also contributed to retardation of bone loss, as demonstrated by the relatively stable bone density in the placebo group as well as by evidence of reduction of biochemical markers of bone resorption. Therefore, calcium supplementation was also necessary in preventing bone loss in Thai postmenopausal osteoporosis. Moreover, the increment of BMD and the reduction of bone resorption marker in the placebo group in this study were greater than those of other previous reports [9,13–15,17,31]. The possible explanation is an adequate vitamin D level in elderly Thais [32–34], whereas the majority of elderly persons in some countries were vitamin D deficient [35–37]. Calcium supplementation in Thai elderly with a relative adequate vitamin D level could enhance intestinal calcium absorption and lead to a consequent decrease in bone turnover that results in an increase in BMD. In addition, the optimum calcium intake in the Thai population through the ages has been expected to be less than those recommended in Caucasians. The total amount of daily calcium intake after calcium supplementation in this study may be optimal to achieve maximum calcium retention in Asians, as recently demonstrated by a balance study in Japanese postmenopausal women [38]. In conclusion, alendronate was effective as an antiresorptive drug. Daily treatment with 10 mg oral alendronate progressively increased bone mass and reduced bone resorption in Thai postmenopausal osteoporosis. It was well tolerated without any serious side effect. Alendronate should be a good alternative for prolonged use of HRT, which has adverse effects that outweigh its benefit, as demonstrated by recent findings from the Women’s Health Initiative Study [6]. Acknowledgments. This work was supported by Merck Sharp & Dohme. We thank Johnson and Johnson (Thailand) for kindly providing the Vitros NTx assay for this study.

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