骨康口服液治疗原发性骨质疏松症（肾阳虚证）临床研究
摘要
目的:
通过临床试验研究,观察骨康口服液治疗原发性骨质疏松症中医辩证为肾阳虚型的临床疗效及安全性,为进一步指导III期临床试验奠定基础。
方法:
本研究采取随机双盲对照的临床实验方法,将纳入病例标准的240例原发性骨质疏松症,中医辨证为肾阳虚证的患者随机分为骨康口服液治疗组和阳性药物仙灵骨葆对照组,参照《中药新药临床指导原则》(2002年试行版)做对照治疗,比较其疗效性与安全性。疗效性观察包括:患者治疗前后临床症状变化,运用双能X线骨密度仪(DEXA)检测治疗前后腰椎及髋部骨密度的变化,治疗前后血钙,磷,碱性磷酸酶的变化。安全性观察包括:用药前和疗程结束时一般体格检查:血,尿,大便常规检查,心电图,肝功能,肾功能检查。
1.病例纳入标准:
(1)符合骨质疏松症西医诊断标准和中医辨证属肾阳虚证候者; (2)年龄在50岁～70岁之间者; (3)自愿作为受试对象,签署知情同意书,并能接受试验药物剂型,保证完成疗程者。
2.病例排除标准:
符合以下任何一条,不得纳入观察病例。(1)不符合上述西医诊断及中医辨证标准; (2)年龄50岁以下,70岁以上者; (3)女性为自然绝经不足2年者; (4)有甲状旁腺功能亢进、骨软化症、类风湿性关节炎、多发性骨髓瘤等继发性骨质疏松症及其它严重合并症者;或晚期畸形、残废、丧失劳动力者; (5)合并有心血管和造血系统等严重原发性疾病者; (6)肝功能ALT或AST为正常上限1.5倍以上;肾功能血肌酐>133umol/L (7)过敏体质者或对本药成分中已知有过敏者; (8)精神病或老年痴呆患者; (9)近三个月内采用激素替代治疗(HRT)和服用降钙素(如:密钙息和益钙宁),近六个月内有连续15天应用双膦酸盐者等; (10)病情危重,难以对新药的有效性和安全性作出确切评价者。
3.病例分组: 240例患者来自华中科技大学协和医院,广东省中医院,福建中医学院附属医院,上海曙光医院等4家医院的门诊和住院病例,均为西医明确诊断为原发性骨质疏松症,中医辩证为肾阳虚证病例。随机分为治疗组(A组)和对照组(B组),两组病例比例为1:1(各120例)
4.治疗方法: (1)治疗组药物:骨康口服液1支+仙灵骨葆胶囊模拟片3颗bid po (2)对照组药物:股康口服液模拟剂1支+仙灵骨葆胶囊3颗bid po以上各组24周为一个疗程。
除规定用药外,观察期间禁止使用其它治疗骨质疏松症的中药和西药。
5.观测指标:
(1)安全性指标:生命体征(呼吸,血压,心率)、血、尿、粪常规、心电图、肝(AST)、肾(BUN, Cr)功能检查。
(2)疗效性观察:中医症候疗效,骨密度(BMD)、血清钙、磷、碱性磷酸酶(ALP)。
结果:
1.骨康口服液可显著改善中医证候,治疗组有效率为87.90%,与对照组90.60%比较,差异无统计学意义(p>0.05)。两组中医症候疗前与疗后相比均有明显改善,有显著性差异(p<0.05);治疗后中医证候总积分两组间比较,无显著性差异(p>0.05)。两组用药前后比较,骨密度改善均有显著性差异(p<0.05);上升值两组间比较,差异无统计学意义(p>0.05)。两组病人用药后指标(Ca,P,ALP)变化程度,经统计学检验,无显著性差异(p>0.05)。
2.所有安全性评价(心电图和实验室检查)指标未发现由治疗前正常转为治疗后异常的。心电图指标标仙灵骨葆组有1例由异常转为正常,骨康口服液组有3例由异常转为正常。
结论:
本次临床研究表明,通过与目前批准上市的治疗骨质疏松症有效治疗药物(仙灵骨葆)对照研究,骨康口服液在目前口服剂量疗程范围内,能有效地改善各项相关实验室指标及缓解证候症状,治疗原发性骨质疏松症。在服药过程当中,对肝、肾功能、血常规等相关安全性指标没有明显影响,是一种安全有效的用药途径,发挥了中医药的优势,为以后的临床试验提供了有效的试验数据,并为临床推广使用提供了有利的理论依据。
Objective:
To investigate the clinical curative effect and safety of the Gukangkoufuye(GKKFY) in Patients with primary osteoporosis through clinical test study, get ready for the III part research of the GKKFY.
Method:
Adopting pairs of blind clinical test method that contrast at random, 240 cases primary OP patients(syndrome of deficiency of kidney), were divided into the GKKFY group(treated with GKKFY) and the control group(treated with XianLingGuBao) at random. Consulting”new traditional Chinese medicine clinical guideline”(try edition 2002) and this study progress of P, the period of treatment of both two groups was six months. Curative effect observation included: the change of patients clinical symptom, the change in bone mineral density (BMD) of lumbar vertebrae and hip by dual energy X-ray absorptiometry (DEXA) and the change of blood calcium, phosphorus and alkaline phosphorus before and after treatment. the security observation included: General physical examination, blood, urine and stool routine, electrocardiogram, liver function and renal function( BUN, Cr) before and after treatment.
1. Select patients:
The patient won’t be brought into clinical examination unless he consistent with the following 3 conditions.
(1) The symptoms Correspond with the diagnostic criteria which this project establishes and the symptoms of primary osteoporosis (syndrome of deficiency of kidney).
(2) The age was among 50-70.
(3) Accepting the informed consent.
2. Delete patients:
According with the following anyone conditions, the patient can’t be brought into clinical examination.
(1) The symptoms cannot correspond with the diagnostic criteria which this project establishes and the symptoms of primary osteoporosis (syndrome of deficiency of kidney).
(2) The age was below 50 or above 70.
(3) Female who was menopause within 2 years.
(4) Someone who has suffered hyperparathyroidism, osteomalacia, arthritis deformans, general lymphadenomatosis and secondary osteoporosis or disabled.
(5) Someone who has severity blood-heart diseases.
(6) The AST or ALT upper to the limit of the normal and Cr>133umol/L.
(7) Someone who was hypersensitiveness.
(8) Someone who was a bedlam or senile dementia.
(9) Someone has taken the HRT or CT during the past 3months, taken the BP for at lest for 15 days during the past 6months.
(10) Someone from who cannot get the conclusion.
3. Grouping principle:
240 patients were come from the Union Hospital and so on 4 hospitals, all patients were accorded with diagnosis standards and were divided randomly into the treatment group and antitheses group, There were 120 patients in each group(1:1) without significant differences in sex, age, symptom pattern among tow groups(P﹥0.05).
4. Treatment project:
(1) Treat group: GKKFY 1 bottle + false XLGB capsule 3 pills, two times per day.
(2) Control group: False GKKFY 1 bottle + XLGB capsule 3 pills, two times per day. 24 weeks was a course of the treatment.
5. Observation index:
(1) Therapeutic efficiency observation: the curative effect of syndrome, the bone density, serum Ca, P, ALP.
(2) Safety observation: the blood-routine, the urine-routine, the stool-routine, electr- ocardiogram, liver function (AST), kidney function (BUN, Cr).
Results:
1. The GKKFY has significant effects in symptom remission, the effective rate of treat group was 87.90%,while the control group’s was 90.60%,there was no statistically significant difference between them(p>0.05). The accumulated points of symptom of traditional Chinese medicine were both statistically significant degraded (p<0.05), but there was no statistically significant difference between this two group (p>0.05). The increase of patient’s bone density in two group was statistically significant (p<0.05). In group comparison, the difference has no statistically significance (p>0.05).The change of lever of Ca, P, ALP have no statistically significant difference in group comparison (p>0.05).
2. Safety analysis: There were no untoward reactions in both treat group and control group in the clinical test.
Conclusions:
GKKFY has a constant effect on the patients of primary osteoporosis in this clinical practice: it can relieve the symptoms and improve physical signs and the related indexes of patients. It is a kind of safe medicine which can educe the preponderance of traditional Chinese medicine and be worth generalizing to clinical use.
通过临床试验研究,观察骨康口服液治疗原发性骨质疏松症中医辩证为肾阳虚型的临床疗效及安全性,为进一步指导III期临床试验奠定基础。
方法:
本研究采取随机双盲对照的临床实验方法,将纳入病例标准的240例原发性骨质疏松症,中医辨证为肾阳虚证的患者随机分为骨康口服液治疗组和阳性药物仙灵骨葆对照组,参照《中药新药临床指导原则》(2002年试行版)做对照治疗,比较其疗效性与安全性。疗效性观察包括:患者治疗前后临床症状变化,运用双能X线骨密度仪(DEXA)检测治疗前后腰椎及髋部骨密度的变化,治疗前后血钙,磷,碱性磷酸酶的变化。安全性观察包括:用药前和疗程结束时一般体格检查:血,尿,大便常规检查,心电图,肝功能,肾功能检查。
1.病例纳入标准:
(1)符合骨质疏松症西医诊断标准和中医辨证属肾阳虚证候者; (2)年龄在50岁～70岁之间者; (3)自愿作为受试对象,签署知情同意书,并能接受试验药物剂型,保证完成疗程者。
2.病例排除标准:
符合以下任何一条,不得纳入观察病例。(1)不符合上述西医诊断及中医辨证标准; (2)年龄50岁以下,70岁以上者; (3)女性为自然绝经不足2年者; (4)有甲状旁腺功能亢进、骨软化症、类风湿性关节炎、多发性骨髓瘤等继发性骨质疏松症及其它严重合并症者;或晚期畸形、残废、丧失劳动力者; (5)合并有心血管和造血系统等严重原发性疾病者; (6)肝功能ALT或AST为正常上限1.5倍以上;肾功能血肌酐>133umol/L (7)过敏体质者或对本药成分中已知有过敏者; (8)精神病或老年痴呆患者; (9)近三个月内采用激素替代治疗(HRT)和服用降钙素(如:密钙息和益钙宁),近六个月内有连续15天应用双膦酸盐者等; (10)病情危重,难以对新药的有效性和安全性作出确切评价者。
3.病例分组: 240例患者来自华中科技大学协和医院,广东省中医院,福建中医学院附属医院,上海曙光医院等4家医院的门诊和住院病例,均为西医明确诊断为原发性骨质疏松症,中医辩证为肾阳虚证病例。随机分为治疗组(A组)和对照组(B组),两组病例比例为1:1(各120例)
4.治疗方法: (1)治疗组药物:骨康口服液1支+仙灵骨葆胶囊模拟片3颗bid po (2)对照组药物:股康口服液模拟剂1支+仙灵骨葆胶囊3颗bid po以上各组24周为一个疗程。
除规定用药外,观察期间禁止使用其它治疗骨质疏松症的中药和西药。
5.观测指标:
(1)安全性指标:生命体征(呼吸,血压,心率)、血、尿、粪常规、心电图、肝(AST)、肾(BUN, Cr)功能检查。
(2)疗效性观察:中医症候疗效,骨密度(BMD)、血清钙、磷、碱性磷酸酶(ALP)。
结果:
1.骨康口服液可显著改善中医证候,治疗组有效率为87.90%,与对照组90.60%比较,差异无统计学意义(p>0.05)。两组中医症候疗前与疗后相比均有明显改善,有显著性差异(p<0.05);治疗后中医证候总积分两组间比较,无显著性差异(p>0.05)。两组用药前后比较,骨密度改善均有显著性差异(p<0.05);上升值两组间比较,差异无统计学意义(p>0.05)。两组病人用药后指标(Ca,P,ALP)变化程度,经统计学检验,无显著性差异(p>0.05)。
2.所有安全性评价(心电图和实验室检查)指标未发现由治疗前正常转为治疗后异常的。心电图指标标仙灵骨葆组有1例由异常转为正常,骨康口服液组有3例由异常转为正常。
结论:
本次临床研究表明,通过与目前批准上市的治疗骨质疏松症有效治疗药物(仙灵骨葆)对照研究,骨康口服液在目前口服剂量疗程范围内,能有效地改善各项相关实验室指标及缓解证候症状,治疗原发性骨质疏松症。在服药过程当中,对肝、肾功能、血常规等相关安全性指标没有明显影响,是一种安全有效的用药途径,发挥了中医药的优势,为以后的临床试验提供了有效的试验数据,并为临床推广使用提供了有利的理论依据。
Objective:
To investigate the clinical curative effect and safety of the Gukangkoufuye(GKKFY) in Patients with primary osteoporosis through clinical test study, get ready for the III part research of the GKKFY.
Method:
Adopting pairs of blind clinical test method that contrast at random, 240 cases primary OP patients(syndrome of deficiency of kidney), were divided into the GKKFY group(treated with GKKFY) and the control group(treated with XianLingGuBao) at random. Consulting”new traditional Chinese medicine clinical guideline”(try edition 2002) and this study progress of P, the period of treatment of both two groups was six months. Curative effect observation included: the change of patients clinical symptom, the change in bone mineral density (BMD) of lumbar vertebrae and hip by dual energy X-ray absorptiometry (DEXA) and the change of blood calcium, phosphorus and alkaline phosphorus before and after treatment. the security observation included: General physical examination, blood, urine and stool routine, electrocardiogram, liver function and renal function( BUN, Cr) before and after treatment.
1. Select patients:
The patient won’t be brought into clinical examination unless he consistent with the following 3 conditions.
(1) The symptoms Correspond with the diagnostic criteria which this project establishes and the symptoms of primary osteoporosis (syndrome of deficiency of kidney).
(2) The age was among 50-70.
(3) Accepting the informed consent.
2. Delete patients:
According with the following anyone conditions, the patient can’t be brought into clinical examination.
(1) The symptoms cannot correspond with the diagnostic criteria which this project establishes and the symptoms of primary osteoporosis (syndrome of deficiency of kidney).
(2) The age was below 50 or above 70.
(3) Female who was menopause within 2 years.
(4) Someone who has suffered hyperparathyroidism, osteomalacia, arthritis deformans, general lymphadenomatosis and secondary osteoporosis or disabled.
(5) Someone who has severity blood-heart diseases.
(6) The AST or ALT upper to the limit of the normal and Cr>133umol/L.
(7) Someone who was hypersensitiveness.
(8) Someone who was a bedlam or senile dementia.
(9) Someone has taken the HRT or CT during the past 3months, taken the BP for at lest for 15 days during the past 6months.
(10) Someone from who cannot get the conclusion.
3. Grouping principle:
240 patients were come from the Union Hospital and so on 4 hospitals, all patients were accorded with diagnosis standards and were divided randomly into the treatment group and antitheses group, There were 120 patients in each group(1:1) without significant differences in sex, age, symptom pattern among tow groups(P﹥0.05).
4. Treatment project:
(1) Treat group: GKKFY 1 bottle + false XLGB capsule 3 pills, two times per day.
(2) Control group: False GKKFY 1 bottle + XLGB capsule 3 pills, two times per day. 24 weeks was a course of the treatment.
5. Observation index:
(1) Therapeutic efficiency observation: the curative effect of syndrome, the bone density, serum Ca, P, ALP.
(2) Safety observation: the blood-routine, the urine-routine, the stool-routine, electr- ocardiogram, liver function (AST), kidney function (BUN, Cr).
Results:
1. The GKKFY has significant effects in symptom remission, the effective rate of treat group was 87.90%,while the control group’s was 90.60%,there was no statistically significant difference between them(p>0.05). The accumulated points of symptom of traditional Chinese medicine were both statistically significant degraded (p<0.05), but there was no statistically significant difference between this two group (p>0.05). The increase of patient’s bone density in two group was statistically significant (p<0.05). In group comparison, the difference has no statistically significance (p>0.05).The change of lever of Ca, P, ALP have no statistically significant difference in group comparison (p>0.05).
2. Safety analysis: There were no untoward reactions in both treat group and control group in the clinical test.
Conclusions:
GKKFY has a constant effect on the patients of primary osteoporosis in this clinical practice: it can relieve the symptoms and improve physical signs and the related indexes of patients. It is a kind of safe medicine which can educe the preponderance of traditional Chinese medicine and be worth generalizing to clinical use.
引文
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[4]林守清,雌激素对骨质疏松的防治及在骨转换中作用[J],中华医学杂志,2005,85(11);728-731
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[1]郝新平,我国骨质疏松症研究水平觅待提高[J],中国医学论坛报,2001,27(23);2-3
[2]林守清,雌激素对骨质疏松的防治及在骨转换中作用[J],中华医学杂志,2005,85(11);728-731
[3] Larsen ER, Mosekilde L, Foldspang A. Vitamin D and caicium supplementation prevents osteoporostic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention stud[J],2004,19;370
[4]林守清,雌激素对骨质疏松的防治及在骨转换中作用[J],中华医学杂志,2005,85(11);728-731
[5]谭锐泉,原发性骨质疏松症病因研究略述[J],中医药学刊,2006,24(7);1283-1284
[6]中国人骨质疏松症建议诊断标准(第二稿),中国骨质疏松杂志,2000,6(1);1-3
[7] Brown JP, Josse RG,Clinical practice guidelines for the diagnosis and management of osteoporosis in Canada,CM AJ, 2002,167(10Suppl );S1-S34
[8] WHO: Guidelines for preclinical evaluation and clinical trials in osteoporosis,Geneva;WHO,1998.59
[9]朱汉民,《原发性骨质疏松症诊疗指南》解读,国际内分泌代谢杂志,2006,26(5);289-294
[10] Cauley J A,Osteoporosis: a world wide disease,Medicograpgy,2004,26;215-220
[11]柯棋,许灼新,周守国,腰椎骨质疏松的MRI诊断[J],现代医用影像学,2002,11(6);241-244
[12]孙洪勋,王乃宏,原发性骨质疏松症研究进展,中国中西医结合影像学杂志,2005(3);44-47
[13]黄公怡,骨质疏松症,中国骨肿瘤骨病[J],2003,2(4);197-200
[14] Peterson JA,Osteoporosis overview[J],Geriatr Nurs,2001,22(1);17-23.
[15]郭世缓,罗先正,邱贵兴,骨质疏松-基础与临床[M],天津:天津科学技术出版社,2001:443-447
[16] Muller K ,Wiesenberg I ,Jaeggi K ,et al . Effects of the bisphosphonate zole-dronate on bone loss in the ovariectomized and in the adjuvant arthritic rat [J].Arzneimittelforschung,1998(48);81-86
[17] Chesnut C H,Skag A,Christiansen C,et al. Effects of oral inbandronate administered daily or intermittently on fracture risk in postmenopausal Osteoporosis [J] Bone Miner Res,2004,19;1241-1249
[18]朱锐,淫羊藿炮制后对小鼠血浆辜酮及附性器官的影响[J],中医中药杂志,1989,14(9);19
[19]张妤维,韩春生,中医对骨质疏松症的认识沿革与擅变[J],中国骨质疏松杂志,1999,5(1);123-124
[20]刘亦恒,臧洪敏,张海英,等,淫羊藿总黄酮对成骨细胞中OPG和RANKL mRNA基因表达影响的实验研究[J],中药材,2005,12(28);1076-1078
[21]杜靖远,沈霖,杨家玉,等,补肾密骨液对大鼠卵巢切除诱导的实验性骨质疏松症的影响,中华骨科杂志,1996,16(7);462
[22]刘剑刚,谢雁鸣,骨碎补总黄酮的活血化瘀作用对实验性微循环障碍和骨质疏松症的影响,中国骨质疏松杂志,2006,2(12);24