The Effect of 2-year Bi-weekly Administration of Alendronate on Bone Mineral Density and Bone Turnover Marker in Postmenopausal
Korean Women Compared with Once-weekly Administration
Il Woo Joo, MD, Han Jin Oh, MD
Department of Family Medicine, Cheil General Hospital, College of Medicine, Kwandong University, Seoul, Korea
알렌드로네이트를 격주 투여한 한국 폐경 여성에서의 골밀도 및 골표지자의 변화
관동대학교 의과대학 제일병원 가정의학교실
주 일 우․오 한 진
목적: 알렌드로네이트 5 mg 매일 투여는 이미 골밀도 소실 예방에 도움이 된다고 알려져 있다. 최근 일본의 pilot study에서는 더욱 소용량인 2.5 mg도 유익한 효과를 나타낸다는 보고가 있었다. 반면 환자의 복용 편의성과 비용 효 과적 측면에서 볼 때, 투약량 뿐만 아니라 투약 간격을 늘리는 것을 고려해 볼 수 있다. 이에 착안하여, 저자들은 알 렌드로네이트 70 mg을 격주 투여하였을 경우의 골밀도와 골표지자 변화를 기존의 방식인 매주 투여한 경우와 비교 하는 연구를 계획하였다.
방법: 골밀도 T score가 <-2.0인 한국 폐경 여성을 대상으로 2년간 알렌드로네이트 70 mg을 격주 투여하였을 경우의 골밀도와 골표지자 변화를 매주 투여한 경우와 비교하였다.
결과: 알렌드로네이트 매주 투여군에서 요추 골밀도의 경우 4.3% 증가하였으며 대퇴부 골밀도의 경우 2.3% 증가하 였다. 반면 격주 투여한 군에서는 요추 골밀도는 0.3% 감소, 대퇴부 골밀도의 경우 1.0% 증가하였다. 골표지자의 경 우 두 군간에 통계적으로 유의한 차이는 보이지 않았다.
결론: 저자들의 연구에서 알렌드로네이트 70 mg 격주 투여의 경우 골밀도 예방의 효과가 뚜렷하지는 않더라도 골량 의 생리적 감소 수준 이하로의 유지는 가능할 것으로 유추된다. 향후 이를 뒷받침하는 대규모의 전향적 연구가 필요 할 것이다.
중심단어: 골다공증, 알렌드로네이트, 골밀도, 골표지자
8)Studies about the prevention and treatment of osteo- porosis in postmenopausal women are being conducted
Corresponding Author: Han Jin Oh, Dept. of Family Medicine, Cheil General Hospital, College of Medicine, Kwandong University, Seoul, Korea
Tel: +82-2-2000-7159, Fax: +82-2-2000-7157 E-mail: [email protected]
throughout the world. In particular, research on the effect of biphosphonates, such as alendronate and risedronate, has been exploring the differentiation of osteoclasts and induced apoptosis of osteoclasts leading to antiresoprtive status in bones after absorption. Alen- dronate acts by targeting farnesyl diphosphate synthase, which make farnesyl diphosphate in the mevalonate
pathway in cytosol1. However, the activity of geranyl- geranyl diphosphonate (GGPP), the downstream product of mevalonate pathway, would be inhibited and cytoskeletal function and survival of osteoclasts are reduced. This mechanism of alendronate makes it anchor on the resorptive surface of bone where it loses its ruffled border which might induce bone resorption to prevents the decrease of bone mineral density2,3. Clinical research has shown that a daily administ- ration of 5 mg of alendronate also indicates a preventive effect on bone loss4. Furthermore, a pilot study in Japan indicates that alendronate dosed 2.5 mg daily is as effective as a 10 mg dose in increasing the bone mineral density with 36 weeks of treatment5. Therefore, it is suggested that a daily dose of 10 mg of alendronate may be an overdose for Japanese patients.
However, a dose of 10 mg of alendronate, which showed a curative effect on low bone mineral density, has shown a similar effect on bone loss to that of a 70 mg weekly dose of alendronate with no significant statistical differences6. So in view of patient’s conve- nience, a weekly dose of 70 mg of alendronate 70 mg is the standard of care.
Since a patient with osteopenia whose T-score of bone mineral density is between -1.0 and -2.5 also has shown an increased risk of fracture, the pre-stage of osteoporosis, “osteopenia”, has been the chief area of our focus. A 70 mg bi-weekly administration of alendronate may able to prevent bone mineral density reduction within the physiologic level as well as a 5 mg daily administration of alendronate. Therefore, we designed a comparative study to measure the changes of bone mineral density and bone turnover marker between a 70 mg weekly administration of alendronate and a 70 mg bi-weekly administration of alendronate for a postmenopausal population in the one of the Women’s Health Care Centers in Seoul.
MATERIALS AND METHODS
1. Subjects
We retrospectively evaluated postmenopausal women with T scores <-2.0 who visited the Health Care Center in Seoul, Korea from March 2003 to October 2005 and were treated with 70 mg of alendronate weekly or biweekly. Among those, we collected the subjects after matching the age and the gender.
During this period, the World Health Organization (WHO) discouraged the use of hormone replacement therapy and, as a result, many women who stopped this therapy and who were appropriate candidates by mam- mographic and transvaginal sonographic findings began an alendronate regimen. Subjects who suffered from diabetes, hyperlipidemia, thyroid disease or who were taking medications that influenced bone metabolism were excluded from evaluation.
2. Methods
The study enrolled subjects with medication com- pliance over 90%. A total of 34 subjects treated weekly with 70 mg of alendronate (Foxamax; MSD) and 27 subjects treated bi-weekly with 70 mg of alendronate (Foxamax; MSD) were evaluated for 2 years. Baseline characteristics,including body weight, body mass index, blood pressure, liver function test and lipid profile, were measured in each group. Bone mineral densities on the lumbar and femoral sites and bone turnover markers, including alkaline phosphatase and dioxypyri- dinolone, were measured and compared with data from a follow-up at one-year.
3. Statistical analysis
All data were analyzed by SPSS for Window 11.5 program. Paired T-tests were used to compare the changes of bone mineral density and bone turnover marker between baseline and one-year follow-up results in each groups with a P value of 0.05 or less after adjusting for age and body mass index. Student T-test
Table 1. Baseline characteristics of the subjects with once-weekly and bi-weekly alendronate 70 mg administrations ALN-weekly
(N=34)
ALN-bi-weekly
(N=27) P value
Weight (kg) BMI (kg/m2) Systolic BP Diastolic BP L-BMD (mg/cm2) F-BMD (mg/cm2) FSH (mg/dL) Estradiol (mg/dL) ALP (mg/dL) DPYD (μg/dL) Sugar (mg/dL) T. Chol (mg/dL) HDL (mg/dL) TG (mg/dL)
57.3±6.3 26.5±2.7 126.7±21.4 76.2±10.8 0.871±0.151 0.690±0.095 67.14±33.92
17.1±1.1 4.27±2.64 0.614±0.012 101.7±9.4
209.8±38.9 59.7±16.1 121.8±61.5
59.0±7.6 25.9±1.9 120.6±19.1 76.5±12.1 0.922±0.125 0.721±0.090 68.66±40.61
19.4±2.4 4.29±2.31 0.617±0.013
98.0±8.0 202.1±33.9 55.7±14.8 130.7±49.3
0.06 0.08 0.47 0.7 0.07 0.12 0.13 0.052 0.26 0.059 0.06 0.13 0.27 0.7 By two-sample t-test.
ALN-weekly: alendronate 70 mg weekly administration, ALN-bi-weekly: alendronate 70 mg bi-weekly administration, BMI:
body mass index, BP: blood pressure, L-BMD: lumbar bone mineral density, F-BMD: femur bone mineral density, FSH:
follicular stimulating hormone, ALP: alkaline phosphatase, DPYD: dioxypyridinolone, T. Chol: total cholesterol, HDL: high density lipoprotein, TG: triglyceride.
were also used to compare the changes of bone mineral density and bone turnover marker between the groups.
RESULTS
1. General baseline characteristics
The mean average age is 52.1±1.1 in the alendronate 70 mg weekly group, and 51.9±2.3 in the alendronate 70 mg bi-weekly group. Treatment groups were similar with regard to demographics and baseline disease characteristics. In addition, we observed no osteopo- rosis-related statistical differences among these groups, such as differences in bone mineral density and biochemical markers of bone turnover (Table 1).
2. Changes of bone mineral density and bone turnover markers
During 2 years, in the alendronate 70 mg weekly group, lumbar bone mineral density increased by 4.3%, and femoral bone mineral density increased by 2.3%.
However, in the alendronate 70 mg bi-weekly group, we observed that lumbar bone mineral density decreased by 0.3%, while femoral bone mineral density increased by 1.0%. Comparing the changes of bone mineral density in each groups, a statistically significant increase of lumbar and femoral density was observed in the alendronate 70 mg weekly group but not in the alendronate 70 mg bi-weekly group (P<0.05). Bone turnover markers, such as alkaline phosphatase, deoxy- pyridinolone, showed a decreasing pattern, but this was not statistically significant (Table 2, 3). However, the percent changes of bone mineral density and bone turnover marker showed statistically significant diffe- rences between the alendronate 70 mg weekly group and bi-weekly groups (P<0.05).
DISCUSSION
Alendronate has been used as an anti-resorptive agent in order to prevent bone loss. In the Fracture Inter-
Table 2. Changes of bone mineral density of the subjects treated with a once-weekly and bi-weekly administration of 70 mg of alendronate
ALN-weekly
(N=34) P value ALN-bi-weekly
(N=27) P value L-BMD %change
F-BMD %change
4.3±0.4 2.3±0.6
0.000 0.000
-0.3±0.1 1.0±0.1
0.581 0.631 By paired T-test in each group.
L-BMD: lumbar bone mineral density (mg/cm2), F-BMD: femur bone mineral density (mg/cm2).
Table 3. Changes of the bone turnover marker of the subjects treated with a once-weekly and bi-weekly administ- ration of 70 mg of alendronate
ALN-weekly
(N=34) P value ALN-bi-weekly
(N=27) P value ALP %change
DPYD %change
-19.2±2.1 3.0±14.1
0.096 0.133
-47.8±12.1 3.2±3.2
0.459 0.766 By paired T-test in each group.
ALP: alkaline phosphatase (mg/dL), DPYD: dioxypyridinolone (mg/dL).
vention Trial, treatment with alendronate in the three- year study reduced the incidence of radiologic vertebral fractures by 47%, clinical vertebral fractures by 54%, and multiple vertebral fractures by 90%. All clinical fractures were reduced by 26%. Among the pre- specified fracture sites evaluated, decreases were observed for hip fractures and wrist fractures in the alendronate groups versus the placebo group7.
Alendronate localizes preferentially on bone resorp- tion surfaces. Four hours after administration, alendro- nate is seen under the osteoclasts and at 12 hours inside cells1. The intracellular target of alendronate is farnesyl diphosphate synthase, an enzyme in the mevalonate pathway required for the synthesis of farnesyl diphosphanate, which is upstream of geranyl- geranyl diphosphate (GGPP). GGPP is used for isopre- nylation of many GTP-binding proteins required for cytoskeletal function, vesicular traffic, and cell sur- vival2. GGPP discourages alendronate inhibition of bone resorption, since it can be prevented by the addition of geranylgeraniol, which is converted in the
cell to GGPP. Consistent with this mode of action, osteoclasts become inactivated after alendronate admini- stration and lose their ruffled border, which depends on vesicular traffic3. After bone resorption stops, bone formation proceeds on the surfaces containing alendro- nate, which is then incorporated inside the matrix where it is no longer pharmacologically active8. The alendronate is then eliminated multi-phasically with a half-life that progressively increasesover a period of weeks9. However, the osteoclasts-acting bone resorption remains about two weeks in bone remodeling site.
With respect to the half-life of alendronate, previous studies suggest that alendronate was not needed daily to prevent bone loss. This was confirmed in several animal models, in which continuous suppression of osteoclastic bone resorption and prevention of bone mass loss has been observed using dosing intervals ranging from twice weekly to monthly. The bi-weekly dosage regimen in animal models resulted in a dose- dependent reduction in bone turnover marker and increases in bone mass10. For the convenience of
patients, a 70 mg weekly administration of alendronate is preferred to daily administration. In subsequent studies, daily administration of 5 mg of alendronate also showed preventive effects on bone loss under the physiologic decreasing rate. Furthermore, the compa- rison studies with an alendronate 5 mg daily group and an alendronate 35 mg weekly group showed similar preventive effects on bone loss according to measure- ments of lumbar and hip bone mineral density11. So in some groups, a 35 mg weekly-administration of alendro- nate might be preferred for its convenience. Moreover, an earlier pilot study in Japan indicates that a daily 2.5 mg dose of alendronate is as effective as a 10 mg dose in increasing the bone mineral density with 36 weeks of treatment5. Therefore, it is suggested that a daily dose of 10 mg of alendronate may be an overdose for Japanese patients. In another study from Japan, a 5 mg daily dose of alendronate significantly increased bone mineral density associated with a marked reduction of the bone turnover rate in osteoporotic patients6. In order to test the above hypotheses, we designed a comparison study between an alendronate 70 mg weekly group and an alendronate 70 mg bi-weekly group which seemed to beadministered by preventive dosage on bone loss, especially enough for Asian patients. The subjects were postmenopausal women who visited the Health Care Center in Seoul and who reported a T score of <2.0 and were administered 70 mg of alendronate weekly or bi-weekly.
In this study, lumbar bone mineral density increased by 4.3%, and femoral bone mineral density increased by 2.3% in the alendronate 70 mg weekly group.
However, in the alendronate 70 mg bi-weekly group, lumbar bone mineral density decreased by 0.3%, while femoral bone mineral density increased by 1.0%.
Comparing the changes of bone mineral density in each groups, a statistically significant increase of lumbar and femoral density was observed in the alendronate 70 mg weekly group, but not in the 70 mg bi-weekly group (P<0.05). Bone turnover markers, such as alkaline
phosphatase and deoxypyridinolone, showed a decrea- sing pattern but were not statistically significant. These results suggest that a 70 mg bi-weekly administration of alendronate might have a maintenance effect on bone mineral density below the physiological decreasing rate.
Bone mineral density measurements are widely used to estimate the risk of osteporotic fractures. However, many fractures occur in women with bone mineral densities above the WHO threshold of -2.5. Data from the National Osteoporosis Risk Assessment (NORA) population showed that 52% of the women experi- encing an incident osteoporotic fracture within one year of XXX had a T score measured peripherally between -1.0 and -2.5, while 82% had a T score>-2.512. In NORA, younger women with low bone mineraldensity had a higher fracture risk than their age-matched peers whose bone mineral density was better. When women aged 50～60 present a T score <-2.0, their long term risk for future fracture is likely to be high, since bone loss would be expected to continue indefinitely without intervention. In the OFELY study from 2005, low bone mineral density, defined as a -2.5<T score, <2.0 was associated with an increased fracture risk with an age-adjusted hazard ratio of 2.513. During a median 9.1 year follow–up period, 8% of incident fractures occurred in women with normal bone mineral density, with 48%
incident fractures in osteopenic women, and 44% in osteoporotic women. This study suggested that in post- menopausal women with bone mineral density values in the osteopenic range, a low bone mineral density also needed preventive intervention to reduce the fracture risk.
Kanis et al. observed an increasing fracture risk during the 10-year follow-up period of the osteopenic postmenopausal women with T scores between -1.5 and -2.5 in Sweden14. According to the above results regarding the fracture risk in osteopenic women, pre- ventive care in the osteopenic stage, the pre-stage of osteoporosis, is highly recommended to reduce the risk of fracture and increase one’s quality of life15,16. For
the convenience of patients as well as for cost-effec- tiveness, increasing the dosing interval for the treatment of osteopenia should be considered. Furthermore, some recent studies have reported osteonecrosis of the jaw in patients with bisphosphonate administration. If possible, patients about to begin oral bisphosphonate therapy for bone loss should have a dental examination in advance.
Some health care professionals even recommend short- term bisphosphonate use where possible17. Bisphospho- nate use, such as alendronate, should be considered carefully to confirm the dosing interval and minimum dose necessary to prevent bone loss.
In conclusion, our findings suggest that a 70 mg bi-weekly administration of alendronate has a an effect of lowering bone loss below the physiologic decreasing rate of bone mass. Although not as strongly as the weekly administration, but one that is below the physiologic decreasing rate of bone mass. However, our study has limitations. First, this study was based on the retrospective data, and we were unable to evaluate the associated factors of bone loss such as diet pattern, exercise, family history and prior fractures. Moreover, the study was limited by a relatively small sample size as the number of subjects with low bone mineral density and short-term whom we were able for follow-up was small. It would be useful for our results to be confirmed in larger, longitudinal studies, which could be designed to better evaluate a 70 mg bi-weekly administration of alendronate and its effect on the prevention of bone loss in osteopenic postmenopausal women.
ABSTRACT
Objectives: The daily administration of 5 mg of alendronate has shown a preventive effect on bone loss.
The results of a pilot study in Japan indicated that a 2.5 mg daily dose of alendronate is as effective as a 10 mg dose in increasing the bone mineral density with 36 weeks of treatment. For the convenience of patients and
cost-effectiveness, increasing the dosing interval should be also considered. Therefore, we designed a compara- tive study to measure the changes of bone mineral density as well as the bone turnover marker between weekly administration of alendronate 70 mg and bi- weekly administration of alendronate 70 mg among a postmenopausal population in the one of the Women’s Health Care Centers in Seoul, Korea.
Methods: We retrospectively evaluated the postme- nopausal women with T scores<-2.0 who were treated with alendronate 70 mg weekly or biweekly for 2 years and compared the changes of bone mineral density and bone turnover marker.
Results: Lumbar bone mineral density was increased by 4.3%, and femoral bone mineral density was also increased by 2.3% in the alendronate 70 mg weekly group. However, in the group administered 70 mg of alendronate bi-weekly, lumbar bone mineral density was decreased by 0.3% and femoral bone mineral density was increased by 1.0%. Comparing the changes of bone mineral density in each group, we observed a statistically significant increase of lumbar and femoral density in the alendronate 70 mg weekly group the alendronate 70 mg bi-weekly group did not show statistical differences. Bone turnover markers, such as alkaline phosphatase and deoxypyridinolone, showed a decreasing pattern, but this also was not statistically significant.
Conclusion: Our study suggested that bi-weekly administration of 70 mg alendronate has a preventive effect on bone loss, but below the physiologic decrea- sing rate of bone mass.
Key Words: Osteoporosis, Alendronate, Bone mine- ral density, Bone turnover marker
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