Effects of alendronate with or without hormone
replacement therapy on bone mineral density in postmenopausal osteoporotic
women
Fariba Almassinokiani 1, Mehrak
Ashouri Movasagh 1*, Ali Moazamipur 2
1
Gynaecology and Obstetrics Department, Iran University of Medical
Sciences, Tehran, Iran
2 Shahid Beheshti University of Medical Sciences, Tehran, Iran
*Corresponding Author: Mehrak Ashouri
Movasagh
* Email: mehrakashouri434@yahoo.com
Abstract
Introduction: Osteoporosis is an important problem in postmenopausal women. The use
of best treatment is crucial to attaining appropriate therapeutic and
prophylactic outcomes. Combination therapy versus single therapy may develop
better results. This study was performed to determine the effects of
alendronate alone versus plus hormone replacement therapy (HRT) on bone mineral
density (BMD) in Iranian postmenopausal osteoporotic women.
Materials and Methods: In this randomized clinical trial 200 consecutive postmenopausal
osteoporotic women since 2018 to 2020 were enrolled and randomly assigned to
receive either alendronate 70 mg alone or plus HRT 0.625 mg CEE and 2.5 mg
medroxyprogesterone acetate. The improvement in BMD, hot flash, vaginal
dryness, dyspareunia, and mood disorders was assessed after 12 months and
compared across the groups. SPSS software by Kolmogorov-Smirnov, Chi-Square,
and Mann-Whitney-U tests.
Results: Complete improvement in BMD was seen in 20 and 47 percent in single
and combination groups, respectively with statistically significant difference
(P=0.001). According to results, the improvements in hot flashes (P=0.048),
vaginal dryness (P=0.001), dyspareunia (P=0.002), and mood disorders (P=0.001)
in women were better in combination group.
Conclusion: The addition of HRT to alendronate can increase the therapeutic
effects on BMD and other symptoms in postmenopausal osteoporotic women and its
use is recommended.
Keywords: Osteoporosis, Menopause, Prophylaxis
Introduction
Postmenopausal age is an important period
of life with initiation by vasomotor symptoms since five to ten years earlier
(1). According to definition by world health organization (WHO) osteoporosis is
bone mineral density (BMD) of 2.5 or more under youth mean measures and is
common among postmenopausal women (1,2). Diagnosis and treatment of
postmenopausal osteoporosis affect the fracture rate and quality of life (1).
Eighty percent of osteoporotic women cases are primary without definite causes
and result from postmenopausal ovarian failure and aging process (1). Screening
and correct selection of high-risk patients is an important issue in patients
with osteoporosis (2). Also, selection of the best treatment modality among
bisphosphonates, parathyroid hormone, calcium, vitamin D, and
hormone-replacement therapy (HRT) is another important problem (2). In cases
with BMD over -1 no treatment is required. In cases with BMD between 1 and 2.5,
treatment is required in cases with fractures. The women with BMD over 2.5
indicate treatment of osteoporosis (2). Since hip fracture is common among women,
the use of prophylactic approaches by bisphosphonates and HRT is crucial (3).
But some studies have recommended not using the HRT alone for this matter (4).
If the goal is risk reduction of vertebral fracture each one of alendronate,
risedronate, raloxifene, and parathyroid hormone is important and in cases,
with non-vertebral fractures, the bisphosphonates are recommended (5). Longer
use in earlier cases can help to further reduction of vertebral fractures (6).
Also, bisphosphonates can decrease the stiffness and pain in the joints in
postmenopausal women (6).
Combined treatments can increase BMD,
bone strength, and bone formation (7). with various effects on different
anatomical regions (8-16). HRT can maintain and increase BMD leading to a significant
decrease in vertebral and non-vertebral fractures (15). Since bisphosphonates
and HRT can affect the osteoclasts and osteoblasts, respectively (9,10). in
cases without response to each one, combination therapy may be useful (11). HRT
and alendronate combination is useful in Eastern Asian patients (12). But the
effect in Middle-Eastern Asian cases is unclear. Regarding the increased rate
of osteoporosis and further morbidity and mortality due to osteoporotic
fractures in postmenopausal women in this study the comparative effects of
alendronate alone or plus HRT on BMD in Iranian postmenopausal osteoporotic
women were determined.
Materials and
Methods
In this randomized clinical trial,
Iranian postmenopausal osteoporotic women since 2018 to 2020 were enrolled.
Postmenopausal status was established if they had amenorrhea length of
minimally 12 months or serum FSH level over 40 IU/L. Among them, 200 consecutive cases with BMD
more than 2 standard deviations under hip/lumbar spinal vertebra versus young
females by DXA method were enrolled. The
cases with background disease or positive drug history (including
HRT/alendronate) in the last year that could affect bone metabolism were
excluded. Cases with contraindication for alendronate/HRT were excluded. The
contraindications for alendronate were drug/ingredient hypersensitivity,
hypocalcemia, active gastrointestinal disorders including dysphagia, esophageal
symptomatic diseases, gastritis, duodenitis, peptic ulcer, and creatinine
clearance between 35 and 60 ml/min. contraindications for HRT were suspected
breast cancer, history of endometrial adenocarcinoma, idiopathic vaginal
bleeding, active hepatic disease, acute thrombotic/thromboembolic disease,
chronic hepatic disease, estrogen-dependent thrombotic/thromboembolic events,
active/previous endometriosis, leiomyoma, uncontrolled hypertension, active
gallbladder disease, estrogen-dependent migraine headache, hyperlipidemia, and
acute intermittent porphyria.
Helsinki Declaration was respected across the study. The informed
consent form was signed by all participating patients. The study was approved
by local ethical committee with code IR.GUMS.REC.1396.459. Women were randomly
assigned to receive either alendronate 70 mg alone or plus HRT 0.625 mg conjugated
equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate. Cases were
learned to use alendronate with high-volume water and non-lying-down position
for minimally 30 minutes. Also, calcium bicarbonate 500 mg/day and regular
exercise were recommended. In the 2nd to 4th lumbar spine
and hip, the BMD was measured by the DXA method in a single hospital by a
unique operator and device initially and after 12 months of treatment. The
improvement of fewer than 15%, 15%-25%, and over 25% was considered negative,
partial, and complete, respectively. Also, the improvement in hot flashes
(subjective), vaginal dryness (subjective), dyspareunia (subjective), and mood
disorders (Beck scale) were compared after 12 months across the groups. The
therapeutic adverse effects were determined in groups.
Data analysis was performed by statistical package for social
sciences (SPSS) software version 24.0 to compare the groups for background and
outcome variables. The utilized tests were Kolmogorov-Smirnov, Chi-Square, and Mann-Whitney-U.
The P values under 0.05 were considered statistically significant.
Results
Table 1. Background variables across the groups.
|
Variable |
Group |
Mean ± Standard Deviation |
P-Value |
|
Age |
Single |
58.2 ± 5.1 |
0.317 |
|
Combination |
57.5 ± 5.3 |
||
|
Menarche age |
Single |
11.8 ± 0.7 |
0.914 |
|
Combination |
11.8 ± 0.7 |
||
|
Menopause age |
Single |
50.3 ± 1.6 |
0.877 |
|
Combination |
50.3 ± 1.6 |
Table
2. Body
mass index across the groups.
|
Group |
Underweight |
|
Normal |
Overweight |
Obese |
P-Value |
|
Single |
2.0% |
|
59.0% |
28.0% |
11.0% |
0.714 |
|
Combination |
1.0% |
|
62.0% |
30.0% |
7.0% |
According to Table 3, the BMD complete improvement was seen in 20 and 47
percent in single and combination groups, respectively with statistically
significant difference (P=0.001). According to Table 4, the improvements in hot
flashes (P=0.048), vaginal dryness (P=0.001), dyspareunia (P=0.002), and mood
disorders (P=0.001) in women were better in combination group.
Table 3. Bone mineral density improvement across the groups.
|
Group |
Negative |
Partial |
Complete |
P-Value |
|
Single |
12.0% |
68.0% |
20.0% |
0.001 |
|
Combined |
4.0% |
49.0% |
47.0% |
Table 4. Improvements in various measures across the groups.
|
Group |
Ne Hot flash |
Dyspareunia |
Vaginal dryness |
Mood disorders |
|
Single |
42.0% |
38.0% |
50.0% |
48.0% |
|
Combined |
56.0% |
61.0% |
71.0% |
71.0% |
|
P-Value |
0.048 |
0.001 |
0.002 |
0.001 |
There were therapeutic adverse effects in 7.0% and 10.0% of patients in
single and combined groups, respectively without significant difference
(P=0.447). The side effects were
headache (1 case), gastrointestinal (2 cases), and skeletal (4 subjects) in
single group, and gastrointestinal (4 cases), skeletal (3 subjects), and
hypersensitivity (3 cases) in combination group (P=0.220).
Discussion
Osteoporosis is an important problem in
postmenopausal women and appropriate therapy is essential in these patients. In
this study, it was shown that the addition of HRT to alendronate resulted in
better improvement in bone mineral density as same as a hot flash, vaginal
dryness, dyspareunia, and mood disorders in postmenopausal women. Dasilva
LLibre et al
(16) reported that combination therapy versus
alendronate alone significantly reduced improvement time. Also, the therapeutic
costs and fracture risk are reduced significantly was decreased that resulted
in a higher quality of life. We could not assess the costs and fracture risk
but in our study, the combination therapy had significantly better outcomes.
Tiras et al (17) reported that alendronate was significantly more effective than HRT and
the combination of them has also more effects. Alendronate is an appropriate
therapeutic option for patients with contraindication or who refuse HRT
therapy. In our study alendronate had good efficacy, especially with HRT
addition. Cortet et al (18) reported that both etidronate and
alendronate significantly increased BMD but the efficacy of alendronate was
higher. Conversely, therapeutic adverse effects and discontinuations for side
effects are higher in the alendronate group. In our study also gastrointestinal
adverse effects were more common but there was no discontinuation case.
Greenspan et al (9) declaimed that alendronate 10 mg daily was superior
to HRT but combination of them was superior to each one alone as same as our
study. Pines and colleagues (19) reported that three and six-month
intervals of measurement of BMD was predictive of outcomes in alendronate
users. In our study 12-month follow-up was useful and showed a significant
difference between combination and single therapy. Eivo et al (20) converse to our study reported that in elderly
postmenopausal women with osteoporosis there was no difference between HRT plus
alendronate therapy versus each one alone.
Tseng and colleagues (21) reported that alendronate plus HRT for three years
was good-tolerated and had a significant effect on BMD in the spinal vertebra
that was in line with our study. Mobley et al (22) reported good efficacy for alendronate alone but the efficacy was
higher for combination therapy of alendronate and HRT. Tuppurainen et al (23) found that HRT combined with clodronate led to no BMD
increase versus HRT alone. Comparison with clodronate alone was possible to
show similar results with our study.
The study by Gambacciani et al (15) demonstrated that addition of HRT to alendronate can
be more useful to prevent osteoporosis as shown in our study. Yoon and
colleagues (16) conversely demonstrated that combination of
alendronate and HRT had no efficacy in Korean postmenopausal women with low
BMD. But there was good efficacy in our population. Rossouw et al (24) compared two groups of 8000 postmenopausal women
including HRT and placebo cases and reported no difference between groups for
cardiovascular effects but also led adverse effects. But in our study addition
of HRT led to better prevention of osteoporosis without an increase in adverse
effects.
There were some limitations in our study; firstly, it was not
programmed for evaluation of fracture risk and bone quality. However,
combination therapy leads to a further reduction in fractures versus a logistic
model, there are few studies about the reduction of fracture risk by combination
therapy. Secondly, the serum level of vitamin D was not measured across the
study. Thirdly it was limited to women that tolerated HRT in a therapeutic
phase that was programmed to reduce lost cases after randomization.
Conclusions
Totally, according to the obtained results in this study, it may be
concluded that addition of HRT to alendronate can increase the therapeutic
effects on BMD and other symptoms in postmenopausal osteoporotic women and its
use is recommended. However further studies with an enrollment of another study
group as HRT alone can be effective for better interpretation of efficacy and
safety of HRT and alendronate combination.
Author contributions
FA and MAM done this research and write manuscript, AM, FA and MAM Guidance and assistance
in data collection and analysis of the results.
Conflict of interest
All authors declare that they have no conflict of interest.
Acknowledgment
The authors are indebted to all
participating women in this study.
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