Arch Osteoporos (2014) 9:189 DOI 10.1007/s11657-014-0189-9
ORIGINAL ARTICLE
Effect of raloxifene hydrochloride on bone mineral density and bone turnover in Kuwaiti postmenopausal women with osteoporosis Ibrahim A. Abdelazim & Khaled M. Abdelrazak & Mohamed Al-Kadi & Amr H. Yehia & Bassam M. Sami Nusair & Mohannad Abu Faza
Received: 10 June 2014 / Accepted: 1 July 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary Osteoporosis is a major cause of mortality and morbidity worldwide. Decreased bone turnover markers and increased lumbar spine and total hip bone mineral density (BMD) in raloxifene-treated women add further support to the idea that raloxifene is an effective well-tolerated option for treating Kuwaiti postmenopausal osteoporosis, suitable for long-term use. Introduction/Purpose Osteoporosis is currently a major cause of mortality, morbidity, and medical expense worldwide, and it is important to investigate therapies for the prevention and treatment of osteoporosis in postmenopausal women. This study was designed to detect the effect of raloxifene hydrochloride on bone mineral density and bone turnover in Kuwaiti postmenopausal women with osteoporosis. Methods Postmenopausal women who were free of severe or chronically disabling conditions, had their last menstrual period at least 2 years before the beginning of the study, had a T score for femoral neck or lumbar spine BMD measurements ≤2.5, and were without fractures were included in this study. One hundred and seventy-six (176) women were included in this study and were divided into two groups; the first group (study) received raloxifene with calcium and vitamin D daily for 12 months, and the second group (control) received only calcium and vitamin D. BMD and bone metabolism markers were measured before and after treatment. I. A. Abdelazim : K. M. Abdelrazak : M. Al-Kadi : A. H. Yehia Ain Shams University, Cairo, Egypt I. A. Abdelazim (*) : M. A. Faza Ahmadi Kuwait Oil Company (KOC) Hospital, P.O. Box 9758, 61008 Ahmadi, Kuwait e-mail: [email protected] B. M. S. Nusair King Hussein Medical Center, Amman, Jordan
Results One year after treatment, BMD of lumbar spine and total hip was significantly increased in study group (3.21±5.4 and 1.62±7.4, respectively) compared to controls (0.9±3.8 and −0.8±5.6, respectively); also, Ward’s triangle and trochanter BMD was significantly increased in study group (4.84±9.3 and 1.78±8.5, respectively) compared to controls (1.53±6.6 and −1. 4±6.4, respectively). C-telopeptide was significantly decreased in study group (121±7.8) compared to control group (1,480±6.3); also, serum osteocalcin was significantly decreased in study group (14.5±8.3) compared to control group (43.8±1.3) 1 year after treatment. Occurrence of fractures during this study was significantly low in raloxifene group compared to controls (0 (0 %) versus 3 (3.6 %), respectively). Conclusions Raloxifene appears to be an effective, welltolerated option for treating osteoporosis in Kuwaiti postmenopausal women, suitable for long-term use. Keywords Raloxifene . Bone mineral density . Turnover . Postmenopausal . Osteoporosis
Introduction Reduced estrogen in postmenopausal women accelerates bone loss and increases risk of fractures [1]. While estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) can prevent postmenopausal bone loss [2, 3], estrogen use may produce undesirable side effects such as vaginal bleeding and breast tenderness. Long-term estrogen use (without concurrent use of progestin) has been reported to cause an increased risk of endometrial cancer and associated with a slight increase in the risk of breast cancer [4, 5]. Raloxifene hydrochloride, a benzothiophene compound, is one of the estrogen receptor modulators (SERMs) acting as an estrogen agonist in
189, Page 2 of 5
some tissues (bone and liver) and as an estrogen antagonist in others (breast and uterus) [6]. Raloxifene has been shown to prevent postmenopausal bone loss in both healthy and postmenopausal women and to reduce the incidence of fracture. Healthy postmenopausal women receiving raloxifene for 24 months showed significant increase in bone mineral density (BMD) of the lumbar spine, hip, and total body [7]. Multi-center, randomized, double-blind multiple outcomes of raloxifene evaluation (MORE) trial showed that 3 years of raloxifene treatment preserved bone density, reduced bone turnover, and reduced the incidence of subsequent vertebral fractures in postmenopausal women with osteoporosis [8]. Analysis of the 4-year data from MORE trial showed a sustained reduction in vertebral fracture in women receiving raloxifene [9–11]. In contrast to estrogen, raloxifene does not stimulate the endometrium and has no stimulatory effect of estrogen on the breast [12, 13]. Osteoporosis is currently a major cause of mortality, morbidity, and medical expense worldwide [14, 15]. Therefore, it is important to investigate therapies for the prevention and treatment of osteoporosis in postmenopausal women. This study was designed to assess the effect of raloxifene hydrochloride on bone mineral density (BMD) and markers of bone turnover in Kuwaiti postmenopausal women with osteoporosis.
Patients and methods This comparative case-controlled study was conducted on Ahmadi hospital, Kuwait Oil Company, Kuwait, over 1 year, after approval of the study protocol by the institute ethical committee. Postmenopausal women who were free of severe or chronically disabling conditions, had their last menstrual period at least 2 years before the beginning of the study, had a T score for femoral neck or lumbar spine BMD measurements ≤2.5, and were without fractures were included in this study after informed consent. One hundred and seventy-six (176) were included in this study and were divided into two equal groups; the first group (study group) received raloxifene 60 mg (Eli Lilly and Company, Indianapolis, USA) with calcium 500 mg and 200 IU vitamin D daily for 12 months, and the second group (control group) received only calcium 500 mg and 200 IU vitamin D daily. Women with abnormal uterine bleeding, suspected or history of carcinoma of the breast or estrogen-dependent neoplasia as endometrial cancer, history of cancer within the previous 5 years, history of deep venous thrombosis, bone disorders other than osteoporosis, treatment with any medications affecting bone metabolism, liver diseases (bilirubin >34 μmol/ l, alanine transaminase >100 U/l, or alkaline phosphatase >300 U/l), and impaired kidney functions (serum creatinine >177 μmol/l) were excluded from this study.
Arch Osteoporos (2014) 9:189
Bone mineral density (BMD) was measured by dualenergy X-Ray absorptiometry (DEXA) using Hologic QDR2000 to test four sites (L1–L4) of the lumbar spine at a posterio-anterial position and four sites of the left hip (femoral neck, Ward’s triangle, trochanters, and intertrochanter). Biochemical markers of bone metabolism, serum osteocalcin, and serum C-telopeptide were analyzed using one-step enzyme-linked immunosorbent assay analysis (Osteometer Biotech Co, Denmark). BMD and serum bone metabolism markers were measured before and after treatment for 12 months. Outcome measures changes in lumbar spine, total hip BMD, and level of biochemical markers of bone metabolism. Sample size justification The required sample size was calculated using G* Power software version 3.17 for sample size calculation (*Heinrich Heine Universität; Düsseldorf; Germany), setting the α-error probability at 0.05, power (1-β error probability) at 0.95 %, and effective sample size (w) at 0.5. The effective size (w) was pffiffiffiffiffiffiffiffiffiffiffiffi calculated as follows: w ¼ X 2 =N , where X [2] is the chisquare test and N is the total sample size. The number of participants needed to produce a statistically acceptable figure was 80 women. Assuming a 10 % drop rate in each group, so the number of women included to produce a statistically acceptable figure was 88 women in each group. Statistical analysis Data were collected, tabulated, then statistically analyzed using the Statistical Package for Social Sciences (SPSS) computer software version 18. Numerical variables were presented as mean and standard deviation (±SD), while categorical variables were presented as number and percentage. Student t test was used for comparison between groups as regards quantitative variables and chi-square test (χ2) was used for comparison between groups as regards qualitative variables. A difference with a P value 0.05) (Table 4).
Discussion One hundred and sixty-six (166) women were included in this study and were divided into two equal groups; the first group (study group) received raloxifene 60 mg with calcium 500 mg and 200 IU vitamin D daily for 12 months, and the second group (control group) received only calcium 500 mg and 200 IU vitamin D daily. BMD of lumbar spine and total hip was significantly increased in study group compared to controls; also, Ward’s triangle and trochanter BMD was significantly increased in study group compared to controls 1 year after treatment.
Variables
Raloxifene (study) group=83 women
Control group=83 women
P value (95 % CI), test used
Lumbar spine, mean±SD
3.21±5.4
0.9±3.8
0.0008b (0.8, 2.3, 3.7), t test
Total hip, mean±SD Femoral neck, mean±SD Ward’s triangle, mean±SD Trochanter, mean±SD
1.62±7.4 1.15±2.5 4.84±9.3 1.78±8.5
−0. 8±5.6 −0.5±1.3 1.53±6.6 −1. 4±6.4
0.006b (0.4, 2.4, 4.3), t test 0a (0.9, 1.6, 2.2), t test 0.001b (0.8, 3.3, 5.7), t test 0.005b (0.89, 3.1, 5.4), t test
189, Page 4 of 5
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Table 3 Changes in biochemical markers of bone metabolism in both studied groups Variables
Raloxifene (study) group=83 women
Control group =83 women
P value
Before treatment After treatment Before treatment After treatment C-telopeptide (pg/l), mean±SD Serum osteocalcin (ng/ml), mean±SD
2.681±2.7
121±7.8
2.755±5.6
1.480±6.3
46.6±5.4
14.5±8.3
45.2±6.7
43.8±1.3
P1=1a (−75.3, −74, −72.6), t test P2=0.02b (−1.361, −135, −1.356), t test P1=0a (0.14, 1.4, 2.65), t test P2=0.02b (−31.5, −29.3, 27.0), t test
t test student t test, P1=P for value of bone metabolism markers before treatment in study group compared to control group, P2=P for value of bone metabolism markers after treatment in study group compared to control group a
Non-significant
b
Significant
Liu and colleagues found that 12 months after treatment of postmenopausal women with raloxifene, both lumbar spine and total hip BMD had increased significantly compared with the placebo [1]. Increases in lumbar spine and total hip BMD have been observed in response to raloxifene treatment in other clinical trials in postmenopausal women with osteoporosis [8, 9, 16]. Since serum C-telopeptide and osteocalcin are biochemical markers of bone turnover, in this study, pre-treatment Ctelopeptide was similar with no significant difference between the two studied groups, but it was significantly decreased in study group (121±7.8) compared to control group (1,480± 6.3) 1 year after treatment; also, pre-treatment serum osteocalcin was similar with no significant difference between the two studied groups, but it was significantly decreased in study group (14.5±8.3) compared to control group (43.8±1.3) 1 year after treatment. The greater decrease in these two markers in the raloxifenetreated subjects indicates that raloxifene treatment causes a decrease in bone turnover, as has been observed in previous studies [8, 9, 16]. The decreased bone turnover observed in control group was probably due to the calcium and vitamin D supplementation received by all subjects in this study. The decrease in bone turnover markers and the increase in BMD in the raloxifenetreated subjects add further support to the idea that raloxifene acts as an anti-resorptive agent on the skeletal system, preserving bone mass, and an efficacious treatment option for osteoporosis. Table 4 Adverse effects recorded in the two studied groups
χ2 chi-square a
Non-significant
Occurrence of fractures during this study was significantly low in raloxifene group compared to controls (zero (0 %) versus three (3.6 %), respectively); also, Ettinger et al. and Delmas et al. concluded that raloxifene reduces the risk of vertebral fracture in postmenopausal women with osteoporosis [8, 9]. Adverse side effects recorded in this study were as follows: nasopharyngitis, muscle cramps, diarrhea, hot flushes, allergic and dermatitis, and there was no significant difference between the two studied groups regarding the recorded adverse effects. Consistent with Ettinger et al. and Delmas et al. studies [8, 9], this study found a higher incidence of hot flushes and muscle cramps in the raloxifene group than controls, but this difference was statistically insignificant. The tolerability of raloxifene is important because long-term compliance is essential for the successful treatment of osteoporosis. The current study confirms that raloxifene is well tolerated in postmenopausal Kuwaiti women with osteoporosis with no serious side effects. These data are consistent with the safety profile demonstrated for Raloxifene in previous clinical trials [7, 8, 10]. Also, previous studies indicate that the long-term use of raloxifene has favorable effect on serum lipid without a significant rise in triglyceride [7, 10, 16]. The effects of raloxifene on serum lipids may explain the decrease in cardiovascular events observed in a subset of women with increased risk for cardiovascular events in the MORE study [11]. However, the actual benefits of raloxifene in preventing cardiovascular disease await confirmation in further studies.
Variables
Raloxifene (study) group=83 women
Control group=83 women
P value (95 % CI), test used
Nasopharyngitis number (%)
17 (20.5 %)
12 (14.6 %)
0.3a (1.96), χ2
4 (4.8 %) 6 (7.2 %) 2 (2.4 %) 0 (0 %)
0.2a (1.96), χ2 0.3a (1.96), χ2 0.2a (1.96), χ2 0.08a (1.96), χ2
Muscle cramps number (%) Diarrhea number (%) Hot flushes number (%) Allergic dermatitis number (%)
8 (9.6 3 (3.6 5 (6.0 2 (2.4
%) %) %) %)
Arch Osteoporos (2014) 9:189
Osteoporosis is a systemic skeletal disease characterized by low BMD and microarchitectural deterioration of bone tissue; the consequent increase in bone fragility greatly increases the risk of fractures, with the major fracture sites in osteoporosis being the hip, vertebrae, and distal radius [17]. Due to increasing population and increased life expectancy, the incidence of osteoporosis is increasing worldwide. In this study, raloxifene increases lumbar spine, total hip, Ward’s triangle, and trochanter BMD and decreases the biochemical markers of bone metabolism. Zheng et al. previously concluded that raloxifene increases lumbar spine and hip BMD in healthy postmenopausal women [15]; also, Liu and colleagues concluded that raloxifene increases lumbar spine and hip BMD and decreases biochemical markers of bone metabolism in postmenopausal women with osteoporosis, indicating that raloxifene provides an effective option for the prevention and treatment of osteoporosis [1]. Zheng et al. previously concluded that raloxifene increases lumbar spine and hip BMD in healthy postmenopausal women [15], also, in this study, raloxifene appears to be an effective, well-tolerated option for treating osteoprosis in Kuwaiti postmenopausal women and suitable for long term use. Acknowledgments Ahmadi Kuwait Oil Company (KOC) Hospital (where the study was conducted) and all authors have contributed significantly and are responsible for the content of this manuscript.Ibrahim A. Abdelazim is responsible for; first concept, study design and analysis of data. Khaled M. Abdelrazak is responsible for; writing manuscript, collection of data and interpretation of manuscript data. Mohamed Al-Kadi is responsible for; writing manuscript and revision before publication. Amr H. Yehia is responsible for; writing manuscript and analysis of data.Bassam M.Sami Nusair is responsible for; intellectual content and final revision before publication. Mohannad Abu Faza is responsible for; intellectual content and statistical analysis of manuscript data.
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6.
7.
8.
9.
10.
11.
12.
13. Conflict of interest None
References 14. 1. Liu JL, Zhu HM, Huang QR, Zhang ZL, Li HL, Qin YJ, Zhang Y, Wei DL, Lu JH, Liu H, Chen XP, Liu YJ, Ekangaki A, Zheng YM, Diez-Perez A, Harper K (2004) Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis: a multi-center, randomized, placebo-controlled clinical trial. Chin Med J (Engl) 117(7):1029–1035 2. Compston JE (1994) Hormone replacement therapy for osteoporosis: clinical and pathophysiological aspects. Reprod Med Rev 3:209–224 3. Col NF, Eckman MH, Karas RH, Pauker SG, Goldberg RJ, Ross EM, Orr RK, Wong JB (1997) Patient-specific decisions about hormone replacement therapy in postmenopausal women. JAMA 277(14): 1140–1147 4. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D (1995) Hormone replacement therapy and endometrial cancer risk: a metaanalysis. Obstet Gynecol 85(2):304–313 5. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson
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KC, Kotchen JM, Ockene J, Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA 288(3):321–333 Bryant HU (2001) Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulator. Rev Endocr Metab Disord 2:129–138 Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C (1997) Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337(23): 1641–1647 Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Glüer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 282(7):637– 645 Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, Reginster JY, Pols HA, Recker RR, Harris ST, Wu W, Genant HK, Black DM, Eastell R, Mulitple Outcomes of Raloxifene Evaluation Investigators (2002) Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 87(8):3609–3617 Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, Shah AS, Anderson PW (1998) Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 279(18):1445–1451 Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, Rautaharju P, Harper KD, MORE Investigators (Multiple Outcomes of Raloxifene Evaluation) (2002) Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (multiple outcomes of raloxifene evaluation) randomized trial. JAMA 287(7):847–857 Boss SM, Huster WJ, Neild JA, Glant MD, Eisenhut CC, Draper MW (1997) Effects of raloxifene hydrochloride on the endometrium of postmenopausal women. Am J Obstet Gynecol 177:1458–1464 Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, Farrerons J, Karasik A, Mellstrom D, Ng KW, Stepan JJ, Powles TJ, Morrow M, Costa A, Silfen SL, Walls EL, Schmitt H, Muchmore DB, Jordan VC, Ste-Marie LG (2001) Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res Treat 65(2):125–134 Cooper C, Campion G, Melton LJ (1992) Hip fractures in the elderly: a world-wide projection. Osteoporosis Int 2:285–289 Zheng SR, Wu YY, Zhang ZL, Yang X, Hui Y, Zhang Y, Chen SL, Den WH, Liu H, Ekangaki A, Stocks J, Harper K, Liu JL (2003) A randomised clinical trial to study the effects of raloxifene hydrochloride on bone mineral density, biochemical markers of bone metabolism and serum lipids in postmenopausal women. Zhonghua Fu Chan Ke Za Zhi 38(4):226–229, Article in Chinese Lufkin EG, Whitaker MD, Nickelsen T, Argueta R, Caplan RH, Knickerbocker RK, Riggs BL (1998) Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 13(11):1747–1754 Genant HK, Cooper C, Poor G, Reid I, Ehrlich G, Kanis J, Nordin BE, Barrett-Connor E, Black D, Bonjour JP, Dawson-Hughes B, Delmas PD, Dequeker J, Ragi Eis S, Gennari C, Johnell O, Johnston CC Jr, Lau EM, Liberman UA, Lindsay R, Martin TJ, Masri B, Mautalen CA, Meunier PJ, Khaltaev N et al (1999) Interim report and recommendations of the world health organization task-force for osteoporosis. Osteoporosic Int 10(4):259–264
ORIGINAL ARTICLE
Effect of raloxifene hydrochloride on bone mineral density and bone turnover in Kuwaiti postmenopausal women with osteoporosis Ibrahim A. Abdelazim & Khaled M. Abdelrazak & Mohamed Al-Kadi & Amr H. Yehia & Bassam M. Sami Nusair & Mohannad Abu Faza
Received: 10 June 2014 / Accepted: 1 July 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary Osteoporosis is a major cause of mortality and morbidity worldwide. Decreased bone turnover markers and increased lumbar spine and total hip bone mineral density (BMD) in raloxifene-treated women add further support to the idea that raloxifene is an effective well-tolerated option for treating Kuwaiti postmenopausal osteoporosis, suitable for long-term use. Introduction/Purpose Osteoporosis is currently a major cause of mortality, morbidity, and medical expense worldwide, and it is important to investigate therapies for the prevention and treatment of osteoporosis in postmenopausal women. This study was designed to detect the effect of raloxifene hydrochloride on bone mineral density and bone turnover in Kuwaiti postmenopausal women with osteoporosis. Methods Postmenopausal women who were free of severe or chronically disabling conditions, had their last menstrual period at least 2 years before the beginning of the study, had a T score for femoral neck or lumbar spine BMD measurements ≤2.5, and were without fractures were included in this study. One hundred and seventy-six (176) women were included in this study and were divided into two groups; the first group (study) received raloxifene with calcium and vitamin D daily for 12 months, and the second group (control) received only calcium and vitamin D. BMD and bone metabolism markers were measured before and after treatment. I. A. Abdelazim : K. M. Abdelrazak : M. Al-Kadi : A. H. Yehia Ain Shams University, Cairo, Egypt I. A. Abdelazim (*) : M. A. Faza Ahmadi Kuwait Oil Company (KOC) Hospital, P.O. Box 9758, 61008 Ahmadi, Kuwait e-mail: [email protected] B. M. S. Nusair King Hussein Medical Center, Amman, Jordan
Results One year after treatment, BMD of lumbar spine and total hip was significantly increased in study group (3.21±5.4 and 1.62±7.4, respectively) compared to controls (0.9±3.8 and −0.8±5.6, respectively); also, Ward’s triangle and trochanter BMD was significantly increased in study group (4.84±9.3 and 1.78±8.5, respectively) compared to controls (1.53±6.6 and −1. 4±6.4, respectively). C-telopeptide was significantly decreased in study group (121±7.8) compared to control group (1,480±6.3); also, serum osteocalcin was significantly decreased in study group (14.5±8.3) compared to control group (43.8±1.3) 1 year after treatment. Occurrence of fractures during this study was significantly low in raloxifene group compared to controls (0 (0 %) versus 3 (3.6 %), respectively). Conclusions Raloxifene appears to be an effective, welltolerated option for treating osteoporosis in Kuwaiti postmenopausal women, suitable for long-term use. Keywords Raloxifene . Bone mineral density . Turnover . Postmenopausal . Osteoporosis
Introduction Reduced estrogen in postmenopausal women accelerates bone loss and increases risk of fractures [1]. While estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) can prevent postmenopausal bone loss [2, 3], estrogen use may produce undesirable side effects such as vaginal bleeding and breast tenderness. Long-term estrogen use (without concurrent use of progestin) has been reported to cause an increased risk of endometrial cancer and associated with a slight increase in the risk of breast cancer [4, 5]. Raloxifene hydrochloride, a benzothiophene compound, is one of the estrogen receptor modulators (SERMs) acting as an estrogen agonist in
189, Page 2 of 5
some tissues (bone and liver) and as an estrogen antagonist in others (breast and uterus) [6]. Raloxifene has been shown to prevent postmenopausal bone loss in both healthy and postmenopausal women and to reduce the incidence of fracture. Healthy postmenopausal women receiving raloxifene for 24 months showed significant increase in bone mineral density (BMD) of the lumbar spine, hip, and total body [7]. Multi-center, randomized, double-blind multiple outcomes of raloxifene evaluation (MORE) trial showed that 3 years of raloxifene treatment preserved bone density, reduced bone turnover, and reduced the incidence of subsequent vertebral fractures in postmenopausal women with osteoporosis [8]. Analysis of the 4-year data from MORE trial showed a sustained reduction in vertebral fracture in women receiving raloxifene [9–11]. In contrast to estrogen, raloxifene does not stimulate the endometrium and has no stimulatory effect of estrogen on the breast [12, 13]. Osteoporosis is currently a major cause of mortality, morbidity, and medical expense worldwide [14, 15]. Therefore, it is important to investigate therapies for the prevention and treatment of osteoporosis in postmenopausal women. This study was designed to assess the effect of raloxifene hydrochloride on bone mineral density (BMD) and markers of bone turnover in Kuwaiti postmenopausal women with osteoporosis.
Patients and methods This comparative case-controlled study was conducted on Ahmadi hospital, Kuwait Oil Company, Kuwait, over 1 year, after approval of the study protocol by the institute ethical committee. Postmenopausal women who were free of severe or chronically disabling conditions, had their last menstrual period at least 2 years before the beginning of the study, had a T score for femoral neck or lumbar spine BMD measurements ≤2.5, and were without fractures were included in this study after informed consent. One hundred and seventy-six (176) were included in this study and were divided into two equal groups; the first group (study group) received raloxifene 60 mg (Eli Lilly and Company, Indianapolis, USA) with calcium 500 mg and 200 IU vitamin D daily for 12 months, and the second group (control group) received only calcium 500 mg and 200 IU vitamin D daily. Women with abnormal uterine bleeding, suspected or history of carcinoma of the breast or estrogen-dependent neoplasia as endometrial cancer, history of cancer within the previous 5 years, history of deep venous thrombosis, bone disorders other than osteoporosis, treatment with any medications affecting bone metabolism, liver diseases (bilirubin >34 μmol/ l, alanine transaminase >100 U/l, or alkaline phosphatase >300 U/l), and impaired kidney functions (serum creatinine >177 μmol/l) were excluded from this study.
Arch Osteoporos (2014) 9:189
Bone mineral density (BMD) was measured by dualenergy X-Ray absorptiometry (DEXA) using Hologic QDR2000 to test four sites (L1–L4) of the lumbar spine at a posterio-anterial position and four sites of the left hip (femoral neck, Ward’s triangle, trochanters, and intertrochanter). Biochemical markers of bone metabolism, serum osteocalcin, and serum C-telopeptide were analyzed using one-step enzyme-linked immunosorbent assay analysis (Osteometer Biotech Co, Denmark). BMD and serum bone metabolism markers were measured before and after treatment for 12 months. Outcome measures changes in lumbar spine, total hip BMD, and level of biochemical markers of bone metabolism. Sample size justification The required sample size was calculated using G* Power software version 3.17 for sample size calculation (*Heinrich Heine Universität; Düsseldorf; Germany), setting the α-error probability at 0.05, power (1-β error probability) at 0.95 %, and effective sample size (w) at 0.5. The effective size (w) was pffiffiffiffiffiffiffiffiffiffiffiffi calculated as follows: w ¼ X 2 =N , where X [2] is the chisquare test and N is the total sample size. The number of participants needed to produce a statistically acceptable figure was 80 women. Assuming a 10 % drop rate in each group, so the number of women included to produce a statistically acceptable figure was 88 women in each group. Statistical analysis Data were collected, tabulated, then statistically analyzed using the Statistical Package for Social Sciences (SPSS) computer software version 18. Numerical variables were presented as mean and standard deviation (±SD), while categorical variables were presented as number and percentage. Student t test was used for comparison between groups as regards quantitative variables and chi-square test (χ2) was used for comparison between groups as regards qualitative variables. A difference with a P value 0.05) (Table 4).
Discussion One hundred and sixty-six (166) women were included in this study and were divided into two equal groups; the first group (study group) received raloxifene 60 mg with calcium 500 mg and 200 IU vitamin D daily for 12 months, and the second group (control group) received only calcium 500 mg and 200 IU vitamin D daily. BMD of lumbar spine and total hip was significantly increased in study group compared to controls; also, Ward’s triangle and trochanter BMD was significantly increased in study group compared to controls 1 year after treatment.
Variables
Raloxifene (study) group=83 women
Control group=83 women
P value (95 % CI), test used
Lumbar spine, mean±SD
3.21±5.4
0.9±3.8
0.0008b (0.8, 2.3, 3.7), t test
Total hip, mean±SD Femoral neck, mean±SD Ward’s triangle, mean±SD Trochanter, mean±SD
1.62±7.4 1.15±2.5 4.84±9.3 1.78±8.5
−0. 8±5.6 −0.5±1.3 1.53±6.6 −1. 4±6.4
0.006b (0.4, 2.4, 4.3), t test 0a (0.9, 1.6, 2.2), t test 0.001b (0.8, 3.3, 5.7), t test 0.005b (0.89, 3.1, 5.4), t test
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Table 3 Changes in biochemical markers of bone metabolism in both studied groups Variables
Raloxifene (study) group=83 women
Control group =83 women
P value
Before treatment After treatment Before treatment After treatment C-telopeptide (pg/l), mean±SD Serum osteocalcin (ng/ml), mean±SD
2.681±2.7
121±7.8
2.755±5.6
1.480±6.3
46.6±5.4
14.5±8.3
45.2±6.7
43.8±1.3
P1=1a (−75.3, −74, −72.6), t test P2=0.02b (−1.361, −135, −1.356), t test P1=0a (0.14, 1.4, 2.65), t test P2=0.02b (−31.5, −29.3, 27.0), t test
t test student t test, P1=P for value of bone metabolism markers before treatment in study group compared to control group, P2=P for value of bone metabolism markers after treatment in study group compared to control group a
Non-significant
b
Significant
Liu and colleagues found that 12 months after treatment of postmenopausal women with raloxifene, both lumbar spine and total hip BMD had increased significantly compared with the placebo [1]. Increases in lumbar spine and total hip BMD have been observed in response to raloxifene treatment in other clinical trials in postmenopausal women with osteoporosis [8, 9, 16]. Since serum C-telopeptide and osteocalcin are biochemical markers of bone turnover, in this study, pre-treatment Ctelopeptide was similar with no significant difference between the two studied groups, but it was significantly decreased in study group (121±7.8) compared to control group (1,480± 6.3) 1 year after treatment; also, pre-treatment serum osteocalcin was similar with no significant difference between the two studied groups, but it was significantly decreased in study group (14.5±8.3) compared to control group (43.8±1.3) 1 year after treatment. The greater decrease in these two markers in the raloxifenetreated subjects indicates that raloxifene treatment causes a decrease in bone turnover, as has been observed in previous studies [8, 9, 16]. The decreased bone turnover observed in control group was probably due to the calcium and vitamin D supplementation received by all subjects in this study. The decrease in bone turnover markers and the increase in BMD in the raloxifenetreated subjects add further support to the idea that raloxifene acts as an anti-resorptive agent on the skeletal system, preserving bone mass, and an efficacious treatment option for osteoporosis. Table 4 Adverse effects recorded in the two studied groups
χ2 chi-square a
Non-significant
Occurrence of fractures during this study was significantly low in raloxifene group compared to controls (zero (0 %) versus three (3.6 %), respectively); also, Ettinger et al. and Delmas et al. concluded that raloxifene reduces the risk of vertebral fracture in postmenopausal women with osteoporosis [8, 9]. Adverse side effects recorded in this study were as follows: nasopharyngitis, muscle cramps, diarrhea, hot flushes, allergic and dermatitis, and there was no significant difference between the two studied groups regarding the recorded adverse effects. Consistent with Ettinger et al. and Delmas et al. studies [8, 9], this study found a higher incidence of hot flushes and muscle cramps in the raloxifene group than controls, but this difference was statistically insignificant. The tolerability of raloxifene is important because long-term compliance is essential for the successful treatment of osteoporosis. The current study confirms that raloxifene is well tolerated in postmenopausal Kuwaiti women with osteoporosis with no serious side effects. These data are consistent with the safety profile demonstrated for Raloxifene in previous clinical trials [7, 8, 10]. Also, previous studies indicate that the long-term use of raloxifene has favorable effect on serum lipid without a significant rise in triglyceride [7, 10, 16]. The effects of raloxifene on serum lipids may explain the decrease in cardiovascular events observed in a subset of women with increased risk for cardiovascular events in the MORE study [11]. However, the actual benefits of raloxifene in preventing cardiovascular disease await confirmation in further studies.
Variables
Raloxifene (study) group=83 women
Control group=83 women
P value (95 % CI), test used
Nasopharyngitis number (%)
17 (20.5 %)
12 (14.6 %)
0.3a (1.96), χ2
4 (4.8 %) 6 (7.2 %) 2 (2.4 %) 0 (0 %)
0.2a (1.96), χ2 0.3a (1.96), χ2 0.2a (1.96), χ2 0.08a (1.96), χ2
Muscle cramps number (%) Diarrhea number (%) Hot flushes number (%) Allergic dermatitis number (%)
8 (9.6 3 (3.6 5 (6.0 2 (2.4
%) %) %) %)
Arch Osteoporos (2014) 9:189
Osteoporosis is a systemic skeletal disease characterized by low BMD and microarchitectural deterioration of bone tissue; the consequent increase in bone fragility greatly increases the risk of fractures, with the major fracture sites in osteoporosis being the hip, vertebrae, and distal radius [17]. Due to increasing population and increased life expectancy, the incidence of osteoporosis is increasing worldwide. In this study, raloxifene increases lumbar spine, total hip, Ward’s triangle, and trochanter BMD and decreases the biochemical markers of bone metabolism. Zheng et al. previously concluded that raloxifene increases lumbar spine and hip BMD in healthy postmenopausal women [15]; also, Liu and colleagues concluded that raloxifene increases lumbar spine and hip BMD and decreases biochemical markers of bone metabolism in postmenopausal women with osteoporosis, indicating that raloxifene provides an effective option for the prevention and treatment of osteoporosis [1]. Zheng et al. previously concluded that raloxifene increases lumbar spine and hip BMD in healthy postmenopausal women [15], also, in this study, raloxifene appears to be an effective, well-tolerated option for treating osteoprosis in Kuwaiti postmenopausal women and suitable for long term use. Acknowledgments Ahmadi Kuwait Oil Company (KOC) Hospital (where the study was conducted) and all authors have contributed significantly and are responsible for the content of this manuscript.Ibrahim A. Abdelazim is responsible for; first concept, study design and analysis of data. Khaled M. Abdelrazak is responsible for; writing manuscript, collection of data and interpretation of manuscript data. Mohamed Al-Kadi is responsible for; writing manuscript and revision before publication. Amr H. Yehia is responsible for; writing manuscript and analysis of data.Bassam M.Sami Nusair is responsible for; intellectual content and final revision before publication. Mohannad Abu Faza is responsible for; intellectual content and statistical analysis of manuscript data.
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13. Conflict of interest None
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