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Volume 5, Issue 3 (2024)
J Clinic Care Skill 2024, 5(3): 165-171 |
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Ethics code: IR.IUMS.FMD.REC.1400.557
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Received: 2024/04/27 | Accepted: 2024/08/23 | Published: 2024/09/20
Received: 2024/04/27 | Accepted: 2024/08/23 | Published: 2024/09/20
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Ansari Damavandi S, Amirkashani D, Tagrian Isfahani M. The Effect of Bisphosphonate with Testosterone on Bone Mineral Density in Male Patients with Thalassemia Major. J Clinic Care Skill 2024; 5 (3) :165-171
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1- “Department of Pediatric Hematology & Oncology, School of Medicine” and “Aliasghar Children’s Hospital”, Iran University of Medical Sciences, Tehran, Iran
2- “Department of Pediatric Metabolic & Endocrine Disease, School of Medicine” and “Aliasghar Children’s Hospital”, Iran University of Medical Sciences, Tehran, Iran
3- “Department of Pediatric Hematology & Oncology, School of Medicine” and “Hakim Children’s Hospital”, Tehran University of Medical Sciences, Tehran, Iran
2- “Department of Pediatric Metabolic & Endocrine Disease, School of Medicine” and “Aliasghar Children’s Hospital”, Iran University of Medical Sciences, Tehran, Iran
3- “Department of Pediatric Hematology & Oncology, School of Medicine” and “Hakim Children’s Hospital”, Tehran University of Medical Sciences, Tehran, Iran
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Introduction
Despite advancements that prolonging the life of patients suffering from thalassemia major, osteoporosis is considered as one of the main problems of these patients. Decreased bone mineral density (BMD) is very common in patients with thalassemia major [1]. Some studies have reported an osteoporosis prevalence of up to 90%, even in patients receiving regular blood transfusions and chelators [2, 3]. In patients with thalassemia, BMD in the lumbar vertebrae and femoral head is less than normal [4]. The pathogenesis of bone changes in thalassemia major is not yet fully understood. Numerous studies have shown that various factors may be involved in the development of bone disease and osteoporosis in thalassemia major including bone marrow expansion, hypogonadism, growth hormone-insulin-like growth factor-1 (IGF-1) insufficiency, cytokine changes, iron accumulation in bone, side effects of deferoxamine and vitamin D deficiency [5-8]. Some of these factors directly or indirectly affect osteoblasts and reduce bone formation, while others often increase osteoclast activity and bone resorption [9].
Increased bone resorption in patients with thalassemia major justifies the need to use bone resorption inhibitors such as bisphosphonates in the treatment of osteoporosis in these patients. Bisphosphonates are analogs of pyrophosphate and potent inhibitors of osteoclast-mediated bone resorption [10]. This effect is achieved by inhibiting osteoclastic maturation, inhibiting the evolution of monocyte precursors to osteoclasts, inducing apoptosis of osteoclasts, and disrupting the attachment of osteoclasts to bone [11]. The use of bisphosphonates is reasonable in patients with markers of increased bone resorption and in low BMD in densitometry [12]. Moreover, normalizing bone resorption and increasing bone density are good alternative treatments to prevent bone fractures, but so far, studies on reducing the risk of bone fractures with these drugs have not been conclusively stated.
Hypogonadism is one of the major causes of bone loss leading to secondary osteoporosis. Pituitary gonadotropic cell hemosiderosis, and iron accumulation in the testes and ovaries play an important role in the pathogenesis of hypogonadism in patients with thalassemia major [13]. Puberty delay and hypogonadism are the most important clinical complications of iron accumulation in the gonads [14]. In this regard, androgens stimulate the proliferation of preosteoblasts and the differentiation of osteoblasts [15]. Studies have shown that in thalassemia patients without hypogonadism, hormone therapy is associated with a lower risk of osteoporosis, which is observed primarily in the lumbar spine. However, in patients with hypogonadism, osteoporosis may become more severe and with significant bone density loss in the femur. In addition, a significant positive correlation between bone density and the length of hormone therapy has been observed [2]. However, in a systematic review, the administration of hormones was useful for the prevention of osteoporosis, but had small effects [16]. In a study, the use of Bisphosphonate improved the Z-score in the femoral neck and lumbar spine [17]. However, in the study by Piriyakhuntorn et al., taking alendronate 70 mg for a duration of 1 year weekly improved the bone marrow density in the lumbar site of patients with thalassemia, but it did not change in the femoral neck density [18]. The use of combined treatments such as bisphosphonate with testosterone may improves osteoporosis outcomes more than either treatment alone, though more research is needed to confirm this. Therefore, the preset research is designed to determine the effect of combined bisphosphonates and testosterone treatment on bone density in patients with thalassemia major.
Materials and Methods
Study design
This quasi-experimental study included a control group, with participants non-randomly allocated to 4 groups: two experimental groups and two control groups. Data were collected from December 2021 to December 2022.
Participants and sampling
The study was performed on patients with thalassemia major referred to the pediatric blood clinic of Ali-Asghar Hospital affiliated with the Iran University of Medical Sciences and Health Services in Tehran, Iran.
The calculated sample size was 40 patients, but the study was conducted with 38 participants.
The participants were selected by convenience sampling method. In this study, two control groups were selected based on eligible criteria voluntary. However, two intervention groups were selected by block randomization sampling method with two block sizes. Online randomization was used to generate random sequences. Therefore, four groups of patients were included in the study including, 1) a hypogonadism group treated with testosterone and alendronate (HTA group, 12 patients), 2) a hypogonadism group treated with testosterone alone (HT group, 12 patients), 3) a non-hypogonadism treated with alendronate (group NHA, number 11), and 4) a hypogonadism group that did not receive any treatment (control group 2 or H group, 5 patients).
This study included male patients with thalassemia major, aged over 13.5 years, who either had hypogonadism (confirmed by blood testosterone, LH, and FSH levels) or did not have hypogonadism. Participants needed to be free of underlying disorders such as thyroid disease, parathyroid disease, renal failure, liver disease, or diabetes mellitus. Patients were excluded if they had abnormal liver enzyme results, renal disorders, abnormal calcium or phosphorus levels, abnormal vitamin D levels, thyroid dysfunction, or a bone density greater than -2.5 SD. Additionally, patients who could not be followed up, did not report consistent drug use, or showed signs of drug intolerance were excluded.
Instruments and measurements
The demography and clinical data were gathered using a form. Before the intervention, the patient’s demographic information (age, weight, height), history and examination information including the presence or absence of pain and tenderness and fractures in the femur neck, pelvis and spine, the presence or absence of hypogonadism based on sex hormone levels, underlying diseases and bone densitometry were assessed in all patients. Bone density was measured using Bone Mineral Densitometry through the Dual-energy X-ray Absorptiometry (DEXA) method, before and 1 year after interventions and compared across the study groups. The BMD test was done in a unique and reliable bone density center which is covered by free for special thalassemia patients. The z-score criteria in the BMD imaging method were used for measuring bone mineral density, which is calculated by the imaging device according to the given global standard definition and written in the radiology report. Also, bone densitometry results at all times of the study were recorded in the demography and clinical form.
Intervention
In the present study, the intervention is bisphosphonate with and without testosterone or testosterone alone. At the beginning of the study, an experienced pediatric endocrinologist examined all males with thalassemia major over 13.5 years of age who were diagnosed with decreased bone density based on their history, physical examination, tests, and densitometry. After randomization, patients in the study groups were intervened and treated as follows:
1- Intervention group 1 (HTA group): a hypogonadism group treated with alendronate (70 mg per week for one year) with testosterone (250 mg every 3 to 4 weeks for one year).
2- Intervention group 2 (HT group): a hypogonadism group treated with testosterone alone (250 mg every 3 to 4 weeks for one year).
3- Control group 1 (NHA group): a non-hypogonadism group treated with alendronate.
4- Control group 2 (H group): a hypogonadism group without any treatment.
All research units of the experimental and control groups in the study were reassessed 1 year after completing the treatment to get a history and re-examination, as well as routine tests and bone densitometry results.
Blinding
A single-blind study was conducted with physician blinding. The closed medicine envelopes were given to a researcher who had no involvement in choosing the type of medicine. After the subjects entered the study and their baseline information was collected by the physician, he sent participants to the researcher to get medicine and the researcher gave one of the envelopes to the patients. In the form that was kept by the researcher, it was specified which medicine each patient had taken.
Assessments
In this study, bone mineral density (BMD) including Lumbar Z score, Hip Z score, and Radius Z score were primary outcomes. The BMD test was performed at the beginning of the study and one year later.
Statistical analysis
For the statistical analysis, the statistical software SPSS version 24.0 was used and p-values of ≤0.05 were considered statistically significant. For statistical analysis, results were presented as mean±standard deviation (SD) for quantitative variables and were summarized by frequency (percentage) for categorical variables. Categorical variables were compared between groups using the chi-square test. Continuous variables were compared using the Two-way ANOVA T-Test and Kruskal-Wallis test whenever the data did not appear to have normal distribution or when the assumption of equal variances was violated across the study groups.
Findings
In the present study, 40 patients with thalassemia were enrolled across four groups, with 38 patients completing the study. Two patients dropped out due to non-adherence to medication (one from the HTA group and one from the HT group). The mean age of participants was 22.46±4.64 years. In the HTA group, 2 individuals (18.2%) had a history of smoking or alcohol use. In the HT group, this was 2 individuals (16.7%). All participants in the H group (5 individuals, 100%) had a history, while in the NHA group, 3 individuals (30%) had such a history. All individuals in the HTA group (11, 100%) reported experiencing pain. In the HT group, 9 individuals (75%) reported pain. In the H group, 4 individuals (80%) reported pain, and in the NHA group, 5 individuals (50%) reported pain. In the HTA group, 3 individuals (27.3%) had a history of Fx.Hx. In the HT group, this was 2 individuals (16.7%). In the H group, 1 individual (20%) had such a history, while in the NHA group, 1 individual (10%) had a history of Fx.Hx. Baseline characteristics, including Sexual Maturity Rate (SMR), history of smoking or alcohol use, and initial frequency of lumbar, pelvic, or extremity pain, did not significantly differ across the four groups. Additionally, there was no difference in testosterone dosage or duration between the groups receiving this treatment (HTA and HT groups; see Table 1).The normality of the data was assessed using the Kolmogorov-Smirnov test.
Table 1. demographic and clinical characteristics of included patients
Significant differences were found in the Lumbar Z score between all four groups after the intervention in patients with thalassemia (p-value=0.001; Table 1). According to the Scheffe Post Hoc test, this difference is related to the two groups HTA and HT (p-value=0.001), between HTA and H (p-value=0.001), between HTA and NHA (p-value=0.001), and also between H and HTA (p-value=0.001).
Moreover, significant improvement in Hip Z score was indicated after the intervention (p-value=0.001; Table 2). According to the Scheffe Post Hoc test, this difference is related to the two groups HTA and HT (p-value=0.001), between HTA and H (p-value=0.001), between HTA and NHA (p-value=0.001), and also between H and HTA (p-value=0.001).
Also, a significant Radius Z score increase after the intervention was observed (p-value=0.005; Table 2). According to the Scheffe Post Hoc test, this difference was related to the two groups of HTA and HT (p-value=0.026) and between HTA and NHA (p-value=0.036).
Table 2. Comparison of the mean difference of Lumbar Z score, Hip Z score and Radius Z score before and after the intervention in four groups of patients
Significant differences were found in the Lumbar Z score between four groups before and after the intervention in groups of patients (Figure 1). Significant differences were found in difference Hip Z scores between four groups before and after the intervention in groups of patients (Figure 2). Moreover, significant differences were found in difference Radius Z score between four groups before and after the intervention in groups of patients (Figure 3).
Figure 1. Comparison of the mean changes of the Lumbar Z score before and after the intervention in four groups of patients (HTA, HT, H, and NHA groups)
Figure 2. Comparison of the mean difference of Hip Z score before and after the intervention in four groups of patients (HTA, HT, H, and NHA groups)
Figure 3. Comparison of the mean changes of Radius Z score before and after the intervention in four groups of patients (HTA, HT, H, and NHA groups)
Discussion
The aim of this study was to determine the effect of bisphosphonates with and without testosterone on bone density in patients with thalassemia major who receive continuous blood transfusions.
Therefore, the researchers addressed in the present study some questions. First, whether the addition of bisphosphonates, including alendronate, to testosterone therapy in patients with hypogonadism can further improve bone density and thus prevent osteoporosis? Second, can bisphosphonate medications be given to thalassemia patients without hypogonadism to help improve bone density in these patients?
The results indicated that co-administration of testosterone and alendronate in patients with thalassemia with hypogonadism had far greater effects than testosterone alone in improving bone density. Obviously, in such patients, administration of testosterone with or without alendronate resulted in a greater improvement than in cases where none of these drugs were administered.
A number of studies have provided conflicting data on the role of testosterone in men's bone health. A study by Amin et al. examined fracture risk in men who were hypogonadal (serum testosterone <3 ng/mL) compared with ogonadal men. It showed that men with the lowest estradiol levels had the highest risk of hip fracture. There was no difference in BMD or hip fracture risk in hypogonadal men compared to ogonadal men, suggesting that testosterone does not play an important role in bone health [19]. Contrary to this study, a study on Australian 609 old men shows that decreased BMD is associated with low testosterone levels, but only low testosterone without estrogen are associated with increased fracture risk, particularly at the hip. This supports the role of testosterone in bone as in the present study [20]. Testosterone stimulates osteoblasts to form trabecular bone and helps osteocytes to prevent trabecular bone loss. Testosterone also has indirect effects on bone through aromatization to estrogen via aromatase [15]. Testosterone-treated hypogonadal men have statistically significant increases in bone density over relatively short periods of time [21]. Wong et al. findings show that hypogonadism reduces the strength of the muscle-bone relationship in men, but enhances the positive correlation of skeletal muscle mass and fat mass in women. As a result, the need to optimize the treatment of hypogonadism in patients with blood transfusion-dependent thalassemia is important [22]. Interestingly, alendronate administration in patients without hypogonadism was also associated with a significant improvement in bone density indices. Bisphosphonates are powerful inhibitors of osteoclasts which inhibits osteoclast absorption and maturation, induction of osteoclast apoptosis and reducing their adhesion to the anti-bone absorptive treatment will replenish the regeneration space, and stabilization of bone structure, bone healing strength and thus reduce the incidence fractures alendronate, neridronate and zoledronic acid seems to be the most effective increased BMD [23]. Similar to the present study, the study by Piriyakhuntorn et al. shows that alendronate 70 mg orally once a week for 12 months effectively improves spine BMD and back pain in thalassemia major patients [18]. Like to the present study, in the study by Skordis et al., after completing drug treatment with two drugs, pamidronate and alendronate, the mean BMD value in the spine and femur area shows a significant improvement [24]. Also, in a study by Giusti, it is shown that the use of bisphosphonates results in a decrease in bone turnover markers, an improvement in BMD in the spine, femur, and total hip positions, as well as an improvement in bone pain in the back and lower back [25]. Moreover, in the study of Tsartsalis et al., the efficacy of zoledronate, alendronate, pamidronate, clodronate, and neridronate in improving bone density is confirmed [26]. Clodronate and neridronate have similar effects to alendronate [26]. A study by Harada et al. on women shows that alendronate may have a positive effect not only on bone, but also on muscle [27]. The study by Orwoll et al. in men with osteoporosis, alendronate (10 mg daily) significantly increases bone density, spine, pelvis and the whole body and helps prevent vertebral fractures and height reduction [28]. In a study by Gaudio et al., daily administration of alendronate is shown to improve bone resorption markers and increase bone density [2]. Also, in a study on the efficacy of zoledronic acid in thalassemia patients, a significant increase in bone density in the lumbar vertebrae is shown [29]. The results of this study will help to find a suitable treatment for osteoporosis and reduce bone pain in patients with thalassemia major. It will also help prevent the progression of osteoporosis at an early age by identifying the risk factors for osteoporosis in these patients.
Therefore, if the results are repeated in other same study, it can be recommended that co-administration of testosterone with alendronate in thalassemia patients with hypogonadism, can be a more effective treatment option than testosterone alone in improving bone density and preventing the progression of osteoporosis as well as pain caused by this disorder. Also, in cases where there is no evidence of gonadal dysfunction, alendronate may be used to help improve bone density and prevent the progression of osteoporosis with a significant reduction in the severity of bone pain, even in patients without hypogonadism.
However, this study had limitations. The sample size was small especially in the control group, because this group was the participants that voluntarily did not receive any treatment. Moreover, there was no guarantee of regular compliance drug use by patients within 1 year.
Conclusion
Adding bisphosphonates to testosterone therapy in thalassemia patients with hypogonadism enhances bone density. Additionally, administering bisphosphonates to thalassemia patients without hypogonadism can be highly effective in improving both bone density and reducing bone pain in these individuals.
Acknowledgments: This article is taken from the professional degree thesis in pediatric Hematologist & Oncologist of Marjan Tagrian conducted at Iran University of Medical Sciences, Iran. The authors would like to thank all participants and personnel at the pediatric blood clinic of Ali-Asghar Hospital affiliated with the Iran University of Medical Sciences and Health Services in Tehran, Iran who helped the researchers of the present study. Moreover, we would like to express our gratitude to the Iran University of Medical Sciences for supporting us.
Ethical Permissions: Written informed consent signed by all participants. Declaration of Helsinki Guideline was considered in this research. Also, the research was approved by the ethics committee of the Iran University of Medical Sciences with the ethical code: IR.IUMS.FMD.REC.1400.557.
Conflicts of Interests: The authors declare that they have no known competing financial interests that could have appeared to influence the work reported in this paper.
Authors' Contribution: Ansari Damavandi Sh (First Author), Main Researcher/Introduction Writer/Discussion Writer (25%); Amirkashani D (Second Author), Methodologist/Assistant Researcher/Statistical Analyst (25%); Tagrian Isfahani M (Third Author), Main Researcher/Introduction Writer/Discussion Writer/Methodologist/Statistical Analyst (50%)
Funding/Support: Nothing declared by the authors.
Despite advancements that prolonging the life of patients suffering from thalassemia major, osteoporosis is considered as one of the main problems of these patients. Decreased bone mineral density (BMD) is very common in patients with thalassemia major [1]. Some studies have reported an osteoporosis prevalence of up to 90%, even in patients receiving regular blood transfusions and chelators [2, 3]. In patients with thalassemia, BMD in the lumbar vertebrae and femoral head is less than normal [4]. The pathogenesis of bone changes in thalassemia major is not yet fully understood. Numerous studies have shown that various factors may be involved in the development of bone disease and osteoporosis in thalassemia major including bone marrow expansion, hypogonadism, growth hormone-insulin-like growth factor-1 (IGF-1) insufficiency, cytokine changes, iron accumulation in bone, side effects of deferoxamine and vitamin D deficiency [5-8]. Some of these factors directly or indirectly affect osteoblasts and reduce bone formation, while others often increase osteoclast activity and bone resorption [9].
Increased bone resorption in patients with thalassemia major justifies the need to use bone resorption inhibitors such as bisphosphonates in the treatment of osteoporosis in these patients. Bisphosphonates are analogs of pyrophosphate and potent inhibitors of osteoclast-mediated bone resorption [10]. This effect is achieved by inhibiting osteoclastic maturation, inhibiting the evolution of monocyte precursors to osteoclasts, inducing apoptosis of osteoclasts, and disrupting the attachment of osteoclasts to bone [11]. The use of bisphosphonates is reasonable in patients with markers of increased bone resorption and in low BMD in densitometry [12]. Moreover, normalizing bone resorption and increasing bone density are good alternative treatments to prevent bone fractures, but so far, studies on reducing the risk of bone fractures with these drugs have not been conclusively stated.
Hypogonadism is one of the major causes of bone loss leading to secondary osteoporosis. Pituitary gonadotropic cell hemosiderosis, and iron accumulation in the testes and ovaries play an important role in the pathogenesis of hypogonadism in patients with thalassemia major [13]. Puberty delay and hypogonadism are the most important clinical complications of iron accumulation in the gonads [14]. In this regard, androgens stimulate the proliferation of preosteoblasts and the differentiation of osteoblasts [15]. Studies have shown that in thalassemia patients without hypogonadism, hormone therapy is associated with a lower risk of osteoporosis, which is observed primarily in the lumbar spine. However, in patients with hypogonadism, osteoporosis may become more severe and with significant bone density loss in the femur. In addition, a significant positive correlation between bone density and the length of hormone therapy has been observed [2]. However, in a systematic review, the administration of hormones was useful for the prevention of osteoporosis, but had small effects [16]. In a study, the use of Bisphosphonate improved the Z-score in the femoral neck and lumbar spine [17]. However, in the study by Piriyakhuntorn et al., taking alendronate 70 mg for a duration of 1 year weekly improved the bone marrow density in the lumbar site of patients with thalassemia, but it did not change in the femoral neck density [18]. The use of combined treatments such as bisphosphonate with testosterone may improves osteoporosis outcomes more than either treatment alone, though more research is needed to confirm this. Therefore, the preset research is designed to determine the effect of combined bisphosphonates and testosterone treatment on bone density in patients with thalassemia major.
Materials and Methods
Study design
This quasi-experimental study included a control group, with participants non-randomly allocated to 4 groups: two experimental groups and two control groups. Data were collected from December 2021 to December 2022.
Participants and sampling
The study was performed on patients with thalassemia major referred to the pediatric blood clinic of Ali-Asghar Hospital affiliated with the Iran University of Medical Sciences and Health Services in Tehran, Iran.
The calculated sample size was 40 patients, but the study was conducted with 38 participants.
The participants were selected by convenience sampling method. In this study, two control groups were selected based on eligible criteria voluntary. However, two intervention groups were selected by block randomization sampling method with two block sizes. Online randomization was used to generate random sequences. Therefore, four groups of patients were included in the study including, 1) a hypogonadism group treated with testosterone and alendronate (HTA group, 12 patients), 2) a hypogonadism group treated with testosterone alone (HT group, 12 patients), 3) a non-hypogonadism treated with alendronate (group NHA, number 11), and 4) a hypogonadism group that did not receive any treatment (control group 2 or H group, 5 patients).
This study included male patients with thalassemia major, aged over 13.5 years, who either had hypogonadism (confirmed by blood testosterone, LH, and FSH levels) or did not have hypogonadism. Participants needed to be free of underlying disorders such as thyroid disease, parathyroid disease, renal failure, liver disease, or diabetes mellitus. Patients were excluded if they had abnormal liver enzyme results, renal disorders, abnormal calcium or phosphorus levels, abnormal vitamin D levels, thyroid dysfunction, or a bone density greater than -2.5 SD. Additionally, patients who could not be followed up, did not report consistent drug use, or showed signs of drug intolerance were excluded.
Instruments and measurements
The demography and clinical data were gathered using a form. Before the intervention, the patient’s demographic information (age, weight, height), history and examination information including the presence or absence of pain and tenderness and fractures in the femur neck, pelvis and spine, the presence or absence of hypogonadism based on sex hormone levels, underlying diseases and bone densitometry were assessed in all patients. Bone density was measured using Bone Mineral Densitometry through the Dual-energy X-ray Absorptiometry (DEXA) method, before and 1 year after interventions and compared across the study groups. The BMD test was done in a unique and reliable bone density center which is covered by free for special thalassemia patients. The z-score criteria in the BMD imaging method were used for measuring bone mineral density, which is calculated by the imaging device according to the given global standard definition and written in the radiology report. Also, bone densitometry results at all times of the study were recorded in the demography and clinical form.
Intervention
In the present study, the intervention is bisphosphonate with and without testosterone or testosterone alone. At the beginning of the study, an experienced pediatric endocrinologist examined all males with thalassemia major over 13.5 years of age who were diagnosed with decreased bone density based on their history, physical examination, tests, and densitometry. After randomization, patients in the study groups were intervened and treated as follows:
1- Intervention group 1 (HTA group): a hypogonadism group treated with alendronate (70 mg per week for one year) with testosterone (250 mg every 3 to 4 weeks for one year).
2- Intervention group 2 (HT group): a hypogonadism group treated with testosterone alone (250 mg every 3 to 4 weeks for one year).
3- Control group 1 (NHA group): a non-hypogonadism group treated with alendronate.
4- Control group 2 (H group): a hypogonadism group without any treatment.
All research units of the experimental and control groups in the study were reassessed 1 year after completing the treatment to get a history and re-examination, as well as routine tests and bone densitometry results.
Blinding
A single-blind study was conducted with physician blinding. The closed medicine envelopes were given to a researcher who had no involvement in choosing the type of medicine. After the subjects entered the study and their baseline information was collected by the physician, he sent participants to the researcher to get medicine and the researcher gave one of the envelopes to the patients. In the form that was kept by the researcher, it was specified which medicine each patient had taken.
Assessments
In this study, bone mineral density (BMD) including Lumbar Z score, Hip Z score, and Radius Z score were primary outcomes. The BMD test was performed at the beginning of the study and one year later.
Statistical analysis
For the statistical analysis, the statistical software SPSS version 24.0 was used and p-values of ≤0.05 were considered statistically significant. For statistical analysis, results were presented as mean±standard deviation (SD) for quantitative variables and were summarized by frequency (percentage) for categorical variables. Categorical variables were compared between groups using the chi-square test. Continuous variables were compared using the Two-way ANOVA T-Test and Kruskal-Wallis test whenever the data did not appear to have normal distribution or when the assumption of equal variances was violated across the study groups.
Findings
In the present study, 40 patients with thalassemia were enrolled across four groups, with 38 patients completing the study. Two patients dropped out due to non-adherence to medication (one from the HTA group and one from the HT group). The mean age of participants was 22.46±4.64 years. In the HTA group, 2 individuals (18.2%) had a history of smoking or alcohol use. In the HT group, this was 2 individuals (16.7%). All participants in the H group (5 individuals, 100%) had a history, while in the NHA group, 3 individuals (30%) had such a history. All individuals in the HTA group (11, 100%) reported experiencing pain. In the HT group, 9 individuals (75%) reported pain. In the H group, 4 individuals (80%) reported pain, and in the NHA group, 5 individuals (50%) reported pain. In the HTA group, 3 individuals (27.3%) had a history of Fx.Hx. In the HT group, this was 2 individuals (16.7%). In the H group, 1 individual (20%) had such a history, while in the NHA group, 1 individual (10%) had a history of Fx.Hx. Baseline characteristics, including Sexual Maturity Rate (SMR), history of smoking or alcohol use, and initial frequency of lumbar, pelvic, or extremity pain, did not significantly differ across the four groups. Additionally, there was no difference in testosterone dosage or duration between the groups receiving this treatment (HTA and HT groups; see Table 1).The normality of the data was assessed using the Kolmogorov-Smirnov test.
Table 1. demographic and clinical characteristics of included patients
Significant differences were found in the Lumbar Z score between all four groups after the intervention in patients with thalassemia (p-value=0.001; Table 1). According to the Scheffe Post Hoc test, this difference is related to the two groups HTA and HT (p-value=0.001), between HTA and H (p-value=0.001), between HTA and NHA (p-value=0.001), and also between H and HTA (p-value=0.001).
Moreover, significant improvement in Hip Z score was indicated after the intervention (p-value=0.001; Table 2). According to the Scheffe Post Hoc test, this difference is related to the two groups HTA and HT (p-value=0.001), between HTA and H (p-value=0.001), between HTA and NHA (p-value=0.001), and also between H and HTA (p-value=0.001).
Also, a significant Radius Z score increase after the intervention was observed (p-value=0.005; Table 2). According to the Scheffe Post Hoc test, this difference was related to the two groups of HTA and HT (p-value=0.026) and between HTA and NHA (p-value=0.036).
Table 2. Comparison of the mean difference of Lumbar Z score, Hip Z score and Radius Z score before and after the intervention in four groups of patients
Significant differences were found in the Lumbar Z score between four groups before and after the intervention in groups of patients (Figure 1). Significant differences were found in difference Hip Z scores between four groups before and after the intervention in groups of patients (Figure 2). Moreover, significant differences were found in difference Radius Z score between four groups before and after the intervention in groups of patients (Figure 3).
Figure 1. Comparison of the mean changes of the Lumbar Z score before and after the intervention in four groups of patients (HTA, HT, H, and NHA groups)
Figure 2. Comparison of the mean difference of Hip Z score before and after the intervention in four groups of patients (HTA, HT, H, and NHA groups)
Figure 3. Comparison of the mean changes of Radius Z score before and after the intervention in four groups of patients (HTA, HT, H, and NHA groups)
Discussion
The aim of this study was to determine the effect of bisphosphonates with and without testosterone on bone density in patients with thalassemia major who receive continuous blood transfusions.
Therefore, the researchers addressed in the present study some questions. First, whether the addition of bisphosphonates, including alendronate, to testosterone therapy in patients with hypogonadism can further improve bone density and thus prevent osteoporosis? Second, can bisphosphonate medications be given to thalassemia patients without hypogonadism to help improve bone density in these patients?
The results indicated that co-administration of testosterone and alendronate in patients with thalassemia with hypogonadism had far greater effects than testosterone alone in improving bone density. Obviously, in such patients, administration of testosterone with or without alendronate resulted in a greater improvement than in cases where none of these drugs were administered.
A number of studies have provided conflicting data on the role of testosterone in men's bone health. A study by Amin et al. examined fracture risk in men who were hypogonadal (serum testosterone <3 ng/mL) compared with ogonadal men. It showed that men with the lowest estradiol levels had the highest risk of hip fracture. There was no difference in BMD or hip fracture risk in hypogonadal men compared to ogonadal men, suggesting that testosterone does not play an important role in bone health [19]. Contrary to this study, a study on Australian 609 old men shows that decreased BMD is associated with low testosterone levels, but only low testosterone without estrogen are associated with increased fracture risk, particularly at the hip. This supports the role of testosterone in bone as in the present study [20]. Testosterone stimulates osteoblasts to form trabecular bone and helps osteocytes to prevent trabecular bone loss. Testosterone also has indirect effects on bone through aromatization to estrogen via aromatase [15]. Testosterone-treated hypogonadal men have statistically significant increases in bone density over relatively short periods of time [21]. Wong et al. findings show that hypogonadism reduces the strength of the muscle-bone relationship in men, but enhances the positive correlation of skeletal muscle mass and fat mass in women. As a result, the need to optimize the treatment of hypogonadism in patients with blood transfusion-dependent thalassemia is important [22]. Interestingly, alendronate administration in patients without hypogonadism was also associated with a significant improvement in bone density indices. Bisphosphonates are powerful inhibitors of osteoclasts which inhibits osteoclast absorption and maturation, induction of osteoclast apoptosis and reducing their adhesion to the anti-bone absorptive treatment will replenish the regeneration space, and stabilization of bone structure, bone healing strength and thus reduce the incidence fractures alendronate, neridronate and zoledronic acid seems to be the most effective increased BMD [23]. Similar to the present study, the study by Piriyakhuntorn et al. shows that alendronate 70 mg orally once a week for 12 months effectively improves spine BMD and back pain in thalassemia major patients [18]. Like to the present study, in the study by Skordis et al., after completing drug treatment with two drugs, pamidronate and alendronate, the mean BMD value in the spine and femur area shows a significant improvement [24]. Also, in a study by Giusti, it is shown that the use of bisphosphonates results in a decrease in bone turnover markers, an improvement in BMD in the spine, femur, and total hip positions, as well as an improvement in bone pain in the back and lower back [25]. Moreover, in the study of Tsartsalis et al., the efficacy of zoledronate, alendronate, pamidronate, clodronate, and neridronate in improving bone density is confirmed [26]. Clodronate and neridronate have similar effects to alendronate [26]. A study by Harada et al. on women shows that alendronate may have a positive effect not only on bone, but also on muscle [27]. The study by Orwoll et al. in men with osteoporosis, alendronate (10 mg daily) significantly increases bone density, spine, pelvis and the whole body and helps prevent vertebral fractures and height reduction [28]. In a study by Gaudio et al., daily administration of alendronate is shown to improve bone resorption markers and increase bone density [2]. Also, in a study on the efficacy of zoledronic acid in thalassemia patients, a significant increase in bone density in the lumbar vertebrae is shown [29]. The results of this study will help to find a suitable treatment for osteoporosis and reduce bone pain in patients with thalassemia major. It will also help prevent the progression of osteoporosis at an early age by identifying the risk factors for osteoporosis in these patients.
Therefore, if the results are repeated in other same study, it can be recommended that co-administration of testosterone with alendronate in thalassemia patients with hypogonadism, can be a more effective treatment option than testosterone alone in improving bone density and preventing the progression of osteoporosis as well as pain caused by this disorder. Also, in cases where there is no evidence of gonadal dysfunction, alendronate may be used to help improve bone density and prevent the progression of osteoporosis with a significant reduction in the severity of bone pain, even in patients without hypogonadism.
However, this study had limitations. The sample size was small especially in the control group, because this group was the participants that voluntarily did not receive any treatment. Moreover, there was no guarantee of regular compliance drug use by patients within 1 year.
Conclusion
Adding bisphosphonates to testosterone therapy in thalassemia patients with hypogonadism enhances bone density. Additionally, administering bisphosphonates to thalassemia patients without hypogonadism can be highly effective in improving both bone density and reducing bone pain in these individuals.
Acknowledgments: This article is taken from the professional degree thesis in pediatric Hematologist & Oncologist of Marjan Tagrian conducted at Iran University of Medical Sciences, Iran. The authors would like to thank all participants and personnel at the pediatric blood clinic of Ali-Asghar Hospital affiliated with the Iran University of Medical Sciences and Health Services in Tehran, Iran who helped the researchers of the present study. Moreover, we would like to express our gratitude to the Iran University of Medical Sciences for supporting us.
Ethical Permissions: Written informed consent signed by all participants. Declaration of Helsinki Guideline was considered in this research. Also, the research was approved by the ethics committee of the Iran University of Medical Sciences with the ethical code: IR.IUMS.FMD.REC.1400.557.
Conflicts of Interests: The authors declare that they have no known competing financial interests that could have appeared to influence the work reported in this paper.
Authors' Contribution: Ansari Damavandi Sh (First Author), Main Researcher/Introduction Writer/Discussion Writer (25%); Amirkashani D (Second Author), Methodologist/Assistant Researcher/Statistical Analyst (25%); Tagrian Isfahani M (Third Author), Main Researcher/Introduction Writer/Discussion Writer/Methodologist/Statistical Analyst (50%)
Funding/Support: Nothing declared by the authors.
Keywords:
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