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Effects of alendronate on bone density in thalassemic patients

Evaluation of alendronate efficacy on bone mineral density in thalassemic
patients
Short title: Alendronate in the treatment of Thalassaemia induced osteoporosis
Abstract:
Introduction :
Thalassaemia is the most common genetic disorder in the world which is
afflicted about 200 million people in this disorder, the etiology of bone disease is
multifactorial. Seemingly, in the setting of increased bone turn-over which manifests by
increased bone resorption and remodeling; bone density decreases. In this research,
Thalassaemia patients with osteoporosis were placed on oral Alendronate therapy for one
year and their pre-and post-study bone mineral densitometry were compared.

Method:
Thalassaemia patients; comprising the major and intermedia types, in the range of
20 to 50 years old were included in the study. They were admitted at three different centers;
Tehran center of Thalassaemia, Iran blood transfusion organization and the rheumatology
clinic of hazard Rasool Akram(s) hospital. First of all, osteoporotic patients diagnosed on the
basis of densitometry were placed on oral regimen of 10mg of Alendronate daily. After a
year, their densitometries were repeated and compared for the changes in BMD(g/cm2) and T-
score. Also, patient’s serum calcium, phosphorus and alkaline phosphatase levels were
measured at the beginning and the end of the year and the results were compared.

Results:
Ninety-six patients of all 120 patients under the scope of the study did their both
first and second bone densitometries which showed increase in BMD and T-score at the
end of the study. Regarding to the BMD increase in patients who used their drugs regularly
and no increase in patients who used drugs irregularly or essentially did not use any

Conclusion:
, we concluded that the role of bisphosphonates for example Alendronate in
increasing bone density of neck of femur and vertebral bones were remarkable without having
dangerous side effects. So early diagnosis; treatment and prophylaxis of osteoporosis in this
group of patients are highly recommendable.

Key word:
Thalassaemia - Osteoporosis - BMD - Alendronate
Introduction
Thalassemia is an inherited anemia in which production of polypeptide chains is disturbed, lead to decline in hemoglobin (Hg) synthesis and makes anemia that in α and β thalassemia Since Hg is responsible for carrying oxygen to the tissues, various symptoms of this disease are created subsequent the anemia. First in 1925 this disease was introduced by a physician called Thomas Koly which was seen in the migrators to the United States like Italians. Thalssa means the sea and hemia is the synonym of anemia [1, 2]. Prevalence of genetic disorder of thalassemia is more in American and Asian regions and in Northern Province of Iran. About 4% of the populations in Iran are carrying gen of Thalassemia shows various symptoms in different organs; bone lesions, hormonal disorders like hypogonadism, hypothyroidism, hypothyroidism, hepatomegaly, spelenomegaly and changes in the personal appearance are some of these symptoms [3, 4]. One of the symptoms of this disease is osteoporosis which is preventable and curable with proper diagnosis by bone mineral densitometry (BMD). Treatment of osteoporosis in these patients includes exercise, consumption of calcium (Ca 1200 mg daily, vitamin D 400 U daily, sexual hormone replacement, adequate treatment with desferal since childhood and using bisphosphonates like alendronate [5, 6]. In one study about osteoporosis on 25 patients with major thalassemia in Italy, alendronate 10 mg/d showed acceptable outcome after two years [7]. In another study on 26 thalassemic patients in Greece, pamidronate IV showed considerable changes in BMD after one year and bone markers also changed [8]. Materials and methods
This study was performed on patients with major thalassemia and intermediate (age range of 20-50 years). Patients who were referred to the thalassemic outpatient clinic of Tehran center of thalassemia, Iran blood transfusion organization and the rheumatology clinic of Rasool At the beginning, bone densitometry of lumbar vertebras L2-L4 and neck of Femur were measured using densitometry system (DXA), Norland type in all the participants and these were repeated after one year treatment with alendronate,and T-Score of Ap spine and Neck of fumre was evaluated. Serum levels of ferritin, calcium, phosphor, alkaline phosphatase were also measured at the beginning and one year after use of alendronate 10 mg. Patients received alendronate 10 mg/d (Modava company, Iran), calcium 100 mg/d (Darupakhsh company, Iran) and vitamin D 400 U (two Ca-D tablets daily). All the patients were visited in 1, 3, 6, 9 and 12 months. Accurate consumption of drugs and their side effects were asked from the participants and were registered in the questionnaire. Consumption of the drug was recorded in three ways: 1. Non-using of the drug that alendronate was discontinued in weeks 1-4 and was not 2. 2. Irregular use that less than 70 mg (7 tablets) was used in a week 3. 3. Regular use that at least 70 mg has been used in a week. In cases of incorrect use of the drug or considerable gastrointestinal complications like gastric ulcer or gastritis, patients were taken apart. BMD was performed at the beginning and after one year treatment and changes more than 3% in spine and more than 6% in the neck of Statistical analysis
Results were reported as mean ± standard deviation (SD) for quantitative variables and percentages for categorical variables. Initial and final values of each variable were compared using paired T test. Statistical significance was based on two-sided design-based tests evaluated at the 0.05 level of significance. All the statistical analyses were performed using SPSS version 16 (SPSS Inc, Chicago, IL, USA) for Windows. Results:
A total number of 120 thalassemic patients with the mean age of 33 years (range, 20-50 years) were enrolled the study. Among them 59 patients (49.2%) were male and 61 others (50.8%) were female. Twenty seven ones (64.2%) has major thalassemia while 43 patients Among all the participants 96 patients complete both initial and final BMD, 14 cases were excluded because of incorrect drug use or drug side effects and one patient died due to The mean initial T-score of the Femur was -2.87±0.94 and its secondary average (after one year) was -2.23±1.01 that based on the paired T test this difference was significant (P<0.001). The mean T-score of the spine was -2.91±0.73 at the initial of the study and it changed significantly in the second measurement to the average of -2.32±0.66 (P<0.01). The mean value of BMD (gr/cm2) in the lumbar spine was 0.682±0.108 in the first session and increased to the 0.773±0.11 that this increase was associated with the regular drug consumption in a way that in 83 patients with regular drug use, 70 ones (95.2%) showed more than 3% increase and in other 4 patients (4.85) decrease occurred. In the group with irregular drug use, 3 patients (60%) had considerable increase while 2 others (40%) had decrease in the Table 1. Association between use of alendronate and BMD changes in the spine.
BMD changes

Irregular use Non-use Regular use
Decrease <3%
Increase >3%
A considerable increase was not seen in 13 (13.5%) patients; among them 7 ones consume drug irregularly. In the group with noticeable increase in BMD, 95.2% (72) patients used drug regularly and 3 ones consumed it irregularly which implies the significant association between regular drug use and increase in BMD (P<0.01). The mean values of BMD (gr/cm2) in Femur were 0.099±0.682 and 0.11±0.750 in the first and second sessions that this increase associates with regular drug use in these patients. In 83 cases with regular drug use, 57 ones (68.7%) showed a considerable increase more than 6% and in 26 (31.3%) decrease in this value was found. In 5 patients with irregular drug consumption only one case (20%) showed a considerable increase while other 4 patients (80%) had decrease in bone densitometry (Table 2). Table 2. Association between use of alendronate and BMD changes in the Femur.
BMD changes

Irregular use Non-use Regular use
Decrease <6%
Increase >6%
About calcium serum level, 95.8% (92) of the patients had normal level (8-10 mg/dl), 2-1% (2) had less than 8 mg/dl and in 2 others it was more than 10 mg/dl which showed no significant association between consumption of alendronate and calcium serum level Sixty three (65.6%) of the patients had normal phosphor serum level (3.5-5 mg/dl) while 33 patients (34.4%) had increase in this value and there was not a significant relation between increase in its serum level and drug consumption. About ALP serum levels with the normal range of 150- 300, 89.6% (86) patients were normal, 1% (1) less than normal and 9.4% (9) were upper than its normal range that its association with drug use was not statistically significant (P=0.986). Discussion
Considering the fact that thalassemic patients are prone to osteoporosis and several factors like bone marrow extension, iron concentration, genetic factors and decline in sexual hormones are effective on it [3, 4]; so screening of these patients and finding their osteoporosis with various diagnostic techniques is necessary that the best method is using DXA system for evaluating bone density [1, 2]. In patients with age of lesser than 30 years old shoud be used of Z-Score of spine and neck of femure.In this study , we measured T- Score of spine and femure.However other methods like sonography are also user for bone density measurement; in a study comparison of DXA system and ultrasound for measuring of bone density showed that ultrasound is weaker than DXA system for bone densitometry [9]. Adequate treatment of the thalassemia since early childhood can decrease incidence of osteoporosis, a study on 35 youngs with thalassemia (5-20 years0 with appropriate treatment showed that they had normal Z-score compared to the control group [6]. In one study in Iran in 2007 by pediatric hematology group on 203 thalassemic patients (10-20 years old), prevalence of osteoporosis was found 7.5% in spine, 10.8% in Femur and 7.9% in both. Affecting factors on osteoporosis in the patients of this study were status of height, weight, delay in puberty or hypogonadism, age at the beginning of desferal use and its duration and serum level of zinc [10]. In a study in 2008 after 2 years use of zoledronic acid annually, it was found that patients who received treatment had significantly better bone density [11]. In a study in Athens in 2006 and Lykone general Hospital, 66 thalassemic patients with osteoporosis were divided in 3 groups; 23 patients in group A that received zoledronic acid 4 mg/IV each 6 months, 21 patients in group B that received zoledronic acid 4 mg/IV each 3 months and 22 patients in group G that received placebo each 3 months. This study was last about one year in which bone density of lumbar spine, neck of Femur and waist of hand, pain and markers of bone resorption (Telopeptide collagen type I), markers of bone formation (alkaline phosphatase) TRAP isoform b and osteocalcin and osteoclast stimulators (Osteopontin, osteoprotegrine) were evaluated before and after treatment protocol. All markers of bone formation and resorption and osteoclast stimulators were considerably high before the study. After treatment bone density of group A did not differ with before but bone pain and bone formation markers and osteoclast stimulators were decreased. In group B there was a considerable increase in bone density of lumbar vertebra with decrease in bone pain and markers for bone formation, resorption and osteoclast stimulators. Patients in group G had no difference in bone density or bon pain, meanwhile showed an increase in bone In a study in university of Messina in 2002, 25 patients with major thalassemia were randomly divided in groups which received placebo, clodrinate 100 mg/IM each 10 days or alendronate 10 mg/d. all the patients received calcium 500 mg and colecalciferolo 400 U with their night food. After 2 years follow up, bone resorption markers in group with placebo did not differ with before treatment but in those groups which were under treatment with clodronate and alendronate these markers were considerably decreased. Osteocalcin and bone formation markers did not show any difference in placebo group before and after the treatment, but in other two groups they decreased a little but not significantly. At the end of the study BMD of lumbar spine in placebo group decreased, in clodronate group did not show a noticeable change, but in alendronate group increased not-significantly. BMD of neck of Femur decreased in placebo group, did not change in clodronate group but increased significantly in alendronate group. During this study no drug side effect was reported and finally it was concluded that in thalassemic patients alendronate can considerable increase In a study in Greece in 2004, 26 thalassemic patients with osteoporosis received pamidronate/IV 30-60 mg for 12 months. BMD, osteoclast function markers (Soluble receptor activator of nuclear factors Kappa B legends (SRANKL), osteoprotegrine (OPG), bone remodeling, N terminal telopeptide collagen type I (NTx), tartrate-resistant acid phosphatase-sb (TRACP-sb), bone alkaline phosphatase (ALP-b) and osteocalcin (OC). A control group of 30 healthy individuals was selected. NTX, TRACP-sb, ALP-b and OC were considerably higher in thalassemic patients compared to the control group, but OPG was lower and SRANKL was in the normal range. After study completion, NTX, TRACP-sb, OPG and OC had been decreased in thalassemic patient and BMD of lumbar spine had been In our study thalassemic patients with osteoporosis that was diagnosed by BMD underwent oral alendronate 70 mg/week. At the beginning and after one year treatment with alendronate BMD was performed (neck of Femur, L2-L4). At the end of the study BMD of Femur and spine increased significantly in group with regular drug use that was significantly associated with increase in T-score and BMD (gr/cm2) (P<0.001). Patients who did not have increase in BMD were among those with the history of irregular drug use, discontinuing of drug because of gastrointestinal complications and low compliance. In comparison with other studies that in two studies they have been used administrative bisphosphonates that are not accessible in our country and we used oral bisphosphonates that are FDA- approved for treatment of osteoporosis, are produced in the country and all the patients were able to prepare the drug. Evaluation of bone resorption and formation markers (except ALP) are used as treatment monitoring in some studies which were not easly accessible in our country and monitoring was performed using BMD in this This study was started with 120 thalassemic patients but only 96 persons complete the second BMD. Because this study was sequential, time restriction for presentation of the study outcomes and at the time of data gathering and analysis time for second BMD in those 24 patients had not common, those patients were taken apart. In this study the rate of fracutres was not evaluated.It's better more studies with attention for risk of fracures in thalasaemia patients is done. There is another limitation about diagnosis of osteoporosis because all densitometry systems are not able to measure BMD in patients under 20 years, so diagnosis of osteoporosis in thalassemic patients whose problem begin at childhood is hard, but in such patients its diagnosis and prevention and treatment should always in mind. Conclusion
Regarding to the BMD increase in patients who used their drugs regularly and no increase in patients who used drugs irregularly or essentially did not use any, we concluded that the role of bisphosphonates in increasing bone density and decreasing risk of fractures in neck of femur, vertebral and non-vertebral bones were remarkable without having dangerous side effects. So, early diagnosis, treatment and prophylaxis of osteoporosis in this group of Acknowledgements
The authors would like to thank Farzan Institute for Research and Technology for technical assistance. Disclosure of Interest
None of the authors has conflict of interest. REFERENCES:
1. David J Weatherall. Disorder of globin synthesis: the thalassaemias.Williams Hematology, seventh Ed. 2006:633-666 2. Caterina B, Organa P, Renzo G.Thalassaemias and related disorder.Wintrobe"s clinical hematology eleventh Ed. 2004,1319- 3. Abolghasemi H, Eshghi P. Thalasemia, 1st ed, 1385, p: 31-40 Bisphosphonates. Endocrinol Metab Clin north Am 1998, 27: 418 – 5. Lasco A, Morabito .N,Gaudib A,et al. Effect of hormonal rreplacement therapy on bone metabolism in young adult with beta– thalassaemia major. Osteoporosis Int 2001; 12: 570 – 575. 6. Christoforidis A,Kazantzidou E,Tsatra H, et al. Normal lumbar bone mineral density in optimally treated children and young adolescents with beta-thalassaemia major. Hormons (Athens)2007 ; 6(4): 334- 7. Morbito N, Lasco A, Gaudio A, et al. Bisphosphonates in the treatment of thalassaemia – induced. osteoporosis int 2002; 13: 644 8. Voskari Dou E, Terpos E, Spina G. Pamidronate is an effective treatment for osteoporosis in patients with B – thalassaemia . Br.J 9. Christoforidis A, Perifanis V,Papadopoulou E,et al. Poor correlations between measurements of bone quality by Quantitative Ultrasound Sonography (QUS) and Dual energy X-ray Absorptiometry (DXA) in Patients with beta-thalassaemia major. 10. Shamshirsaz AA,Bekheirnia MR,kamgar M, et al. Bone mineral density in Iranian adolescents and young adults with beta- thalassaemia major. Pediatr-Hematol Oncol. 2007,24(7):469-79. 11. Voskaridou E,Christolas D. Konstantinidou M,et al. Contineous improvement of bone mineral density two years post zoledronic acid discontinuation in patients with thalassaemia-induced osteoporosis: long-term follow-up of a randomized, placebo- controlled trial. Haematologica 2008 , 93(10):1588-90. 12. Voskaridou E ,Anagnostopolus A,Constantopolus K. Zoledronic acid for the treatment of osteoporosis in patients with B – thalassaemia . J. Hematologica 2006; 91: 1193 – 1202.

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