基于发展模型和混合效应比例优势模型的PMOP中医综合方案疗效评价研究
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摘要
随着老龄化社会的到来,妇女因绝经后而引发的骨质疏松症的比率越来越高,已经成为全球迫切需要解决的一个公众健康问题。国外学者统计,全世界约有1／3的绝经妇女会受到不同程度骨质疏松的困扰,其骨折发生率远远超过肺癌、脑卒中及心脏病的发生率,这给家庭和社会都带来严重的健康及经济压力。
现有许多研究均认为疼痛是骨质疏松症最常见、最主要的症状,在诊断标准中骨密度的诊断一直被公认为黄金标准。绝经后骨质疏松(PMOP)患者中所表现出中医特有的症状或证候是否与骨密度有关,能否可以作为PMOP早期诊断或判断骨量丢失程度的参考指标之一,这是本课题尝试探讨的问题之一。
此外,针对PMOP的治疗,现代医学多采用骨吸收抑制剂或骨形成促进剂等生化制剂,剂量难以控制,长期服用有一定的毒副作用,临床疗效也不显著。PMOP患者在骨折发生前,大量分散聚集在社区中,在社区开展相关临床研究有一定的示范意义。因此,我们在证候学研究的基础上,制定并完善一套具有中医特色的综合干预方案,在社区对患者进行示范性临床干预研究,以期减少患者痛苦、提高临床疗效,并对其疗效评价方法进行探索性研究。该研究具有一定的社会学意义以及推广价值。
1研究目的
探讨PMOP中医症状、中医证候与骨密度不同阶段之间的相关关系；在社区针对PMOP患者开展中医综合方案干预下的示范性研究,探索性采用发展模型和混合效应比例优势模型对综合方案进行疗效评价研究。
2研究方法
2.1在社区招募患者,共入组患者245例,采集相关临床数据,录入并建立数据库。采用卡方检验和有序Logistic回归,分析中医症状、中医证候与骨密度不同阶段之间的关系。
2.2采用前瞻性类试验研究设计,在社区开展治疗PMOP的临床研究。试验组(20例),对照组(20例)。试验组采用中医综合干预方案,方案包括中药免煎颗粒剂(淫羊藿、枸杞子、丹参),配合传统运动八段锦,以及乌骨鸡汤为主要原料的药膳进行协同治疗；对照组采用单一口服钙制剂(钙尔奇D600)。两组观察疗程均为6个月。疗效评价指标为视觉模拟疼痛评分(VAS)、中医症状及骨密度值。疗效评价方法：采用发展模型和混合效应比例优势模型。
3研究结果
3.1中医症状、中医证候与骨密度不同阶段的相关性研究结果
3.1.1将245例绝经后骨量异常的患者,按照骨密度的T值,分为骨量减少、骨质疏松、严重骨质疏松三个阶段。按照症状积分排序：腰膝酸软(598分)、骨痛(516分)、下肢拘挛(502分)、畏寒肢冷(474分)等症状积分较高。下肢拘挛与骨密度不同阶段存在一定关系,且有统计学差异(P<0.05)。腰膝酸软、骨痛、畏寒肢冷、健忘与骨密度不同阶段相关性没有统计学差异(P>0.05)。
3.1.2将245例患者的证候因素按照肾阳虚证、肾阴虚证、血瘀证进行分类。通过有序Logistic回归分析,结果显示三种证候因素与骨密度不同阶段存在相关关系,且有统计学差异(P<0.01)。肾阳虚患者各部位的骨密度值皆低于肾阴虚、血瘀证患者各部位的骨密度值,且有统计学差异(P<0.01)。在骨量减少阶段,患者以血瘀证居多(占76.6%)；在骨质疏松阶段,患者以肾阳虚(49.1%)与血瘀证(33.3%)居多,肾阴虚证(17.6%)较少；在严重骨质疏松阶段,患者以肾阳虚证居多(占80%),且有统计学差异(P<0.05)。
3.2中医综合干预方案的评价结果
3.2.1试验组相对对照组,VAS评分的平均结局分值有更多下降,额外下降的0.23分,有统计学差异(P<0.05)；中医症状积分的平均结局分值有更多下降,额外下降的0.78分,有统计学差异(P<0.05)。两组对下肢拘挛、畏寒肢冷、骨痛、腰膝酸软症状均有一定的缓解作用,但试验组更优于对照组,优于对照组的估计参数分别是0.55、0.40、0.32、0.25,具有统计学差异(P<0.05)；试验组对足跟痛、盗汗、少气懒言、健忘等症状有所改善,而对照组无改善,两组具有统计学差异(P<0.05)。
3.2.2对于减缓骨密度的下降,试验组疗效优于对照组,且有统计学差异(P<0.05)。对于腰椎骨密度的改善,试验组优于对照组,且有统计学差异(P<0.05)。对于股骨颈、股骨粗隆、大转子、Wards三角区骨密度的改善,虽然两组结果在统计学上没有差异(P>0.05),但是从描述统计中可以表明试验组患者的骨密度增长值相对较大,同时骨密度减少的患者也少于对照组,具有一定的临床意义。
4结论
4.1下肢拘挛与骨密度存在相关关系,可以作为早期诊断PMOP的参考指标之一。PMOP的不同证候与骨密度不同阶段之间存在着一定的相关性。骨量减少人群多表现为血瘀证,骨质疏松症或严重骨质疏松症人群多表现为肾阳虚证。患者的不同证候可以作为判断骨量丢失程度的参考指标之一。4.2在社区进行的临床研究,适宜采用前瞻性类试验的设计方法,中医综合干预方案对患者疼痛的缓解、症状的改善更优于单一钙剂的疗效,对延缓骨密度的下降,或提高部分受试者的骨密度值也有一定的疗效。
4.3发展模型和混合效应比例优势模型是适用于对临床试验重复测量数据进行疗效评价的统计学方法。
本研究将中医综合干预方案应用于PMOP治疗,并在社区开展前瞻性类试验,对临床试验重复测量数据采用发展模型和混合效应比例优势模型进行疗效评价,具有一定的创新性。
With the arrival of aging society, the ratio of postmenopausal osteoporosis(PMOP) increasing has become an urgent need to address global public health problems. The most serious complication of osteoporosis is fracture. The fracture incidence is far more than lung cancer, stroke and heart disease incidence, which bring the family and community serious health and economic pressure.
There are many researches show that the pain is the most common and the most important symptoms of PMOP. The diagnosis of bone mineral density(BMD) has been recognized as the gold standard of the diagnostic criteria. Are there any relationship between the symptoms and BMD; any relationship between syndromes and BMD, whether if it can be used as one of the early diagnosis or the determine reference which can judge the extent of bone loss.
Currently, the treatment for PMOP, bone resorption inhibitor and bone formation promoting are used in Modern Medicine. there are difficult to control the Dose of the Biological agents, even there are certain side effects with long-term use. Therefore based on the syndrome, we carry out a demonstration study of the integrated project in the community and exploratory the research on clinical effectiveness evaluation of PMOP with integrated project in TCM.
1 Objectives
Study the relationship which between symptoms of PMOP and bone mineral density; study the relationship which between syndromes of PMOP and bone mineral density. Carry out a demonstration study of the integrated project in the community and exploratory the research on clinical effectiveness evaluation of PMOP with integrated project in TCM based on the growth model and the mixed effects proportional odds model.
2 Methods
2.1 There are 245 patients were enrolled in the community,then we collected、inputed clinical datas and established databases. Using chi-square test and Logistic regression to observe the the relationship between clinical symptoms and bone mineral density; between syndromes and bone mineral density.
2.2 Design a prospective quasi-experimental which treat PMOP in the community. By SAS9.1.3 software, the ratio of the experimental group (20 cases) and control group (20 cases)is 1:1, the baseline of the two groups are consistent. Experimental group received an integrated project which include traditional chinese medicine、sports and diet; the control group received Caltrate D600. Two groups were observed for 6 months. Evaluation standards for the visual analog pain score (VAS), clinical symptoms and bone density. Clinical Evaluation Methods:the Growth model and mixed effects proportional odds model.
3 Resulets
3.1 clinical symptoms, syndromes associated with bone mineral density at different stages of research
3.1.1 245 cases of abnormal bone mass in postmenopausal patients, according to T-bone mineral density values were divided into three stages:bone loss, osteoporosis, severe osteoporosis. According to symptom scores:weak waist (598 points), pain (516 points), lower limb Spasm (502 points), aversion to cold (474 points), score higher. There is a certain relationshipat spasm and bone mineral density at different stages of lower limb, and there is significant difference (P<0.05). Waist and knee weakness, bone pain, aversion to cold, forgetfulness associated with different stages of bone mineral density was not statistically significant (P>0.05).
3.1.2 245 cases of patients with the syndrome factors in accordance with the deficiency, Kidney Yin Deficiency, blood.stasis syndrome was classified. Logistic regression analysis through the orderly, the results show that three kinds of syndromes and bone mineral density at different stages of factors correlated, with statistical difference (P <0.01). The bone mineral density values of Kidney yang deficiency patients is less than yin deficiency and blood stasis syndrome of bone mineral density in different parts, and there is significant difference (P<0.01). Patients with blood stasis are majority (76.6%) at bone loss stage; Patients with deficiency (49.1%) and blood stasis (33.3%) in kidney yin deficiency syndrome (17.6%) are less at osteoporosis stage; at severe osteoporosis stage, the majority of patients with kidney yang deficiency syndrome (80%), with statistical difference (P<0.05).
3.2 Traditional comprehensive intervention program evaluation results
3.2.1 Experimental group compared to control group, VAS scores decreased an average outcome scores more, and an additional drop of 0.23 points was significantly different (P<0.05); TCM symptom score, the average outcome score dropped more additional 0.78 points decline, with significant difference (P<0.05)., There is a certain relieve at spasm of the lower limb group, aversion to cold, bone pain, weak waist in the two groups, but the experimental group was better than the control group, the estimated parameters. better than the control group were 0.55,0.40,0.32,0.25 with significant difference (P<0.05); Experimental group on heel pain, night sweats, less gas lazy words, forgetfulness and other symptoms has improved, while the control group had no improvement, the two groups were statistically different (P<0.05).
3.2.2 For the slow decline in bone mineral density, experimental group was better than the control group, with statistical difference (P<0.05). For the lumbar spine bone mineral density improvement in the experimental group was better than the control group, with statistical difference (P <0.05). For the femoral neck, femoral trochanter, greater trochanter, Wards triangle bone mineral density improvement, although the two sets of results were not statistically different (P>0.05), but from the description that the test statistics can increase the value of bone mineral density in patients relatively large, while in patients with reduced bone mineral density than the control group also has some clinical significance.
4 Conclusions
4. IThere are the relationship between leg cramps and BMD, leg cramps can be the reference indicator of early diagnosis. There are a certain correlation between the different syndromes of PMOP and BMD. Most people of bone loss showed blood stasis syndrome, most people of osteoporosis or severe osteoporosis showed deficiency syndrome. Different Syndromes can be one of the reference indicator of degree of bone loss.
4.2 In the community, the forward-looking of quasi-experiment is an appropriate design method during the clinical trials;with the traditional comprehensive intervention program, the pain relief, the symptoms improvement of the patients are better than with only Calcium. Slow decline in bone mineral density, also and even improve bone density values also have a certain effect.
4.3 The growth model and the mixed effects proportional odds model is applicable to evaluate the clinical efficacy with repeated measurements data.
In this study, Innovation presence the treatment method of PMOP with the comprehensive intervention program; the conduct of the the forward-looking of quasi-experiment in the communities; the evaluate method of the repeated measurements data with the growth model and the mixed effects proportional odds model
现有许多研究均认为疼痛是骨质疏松症最常见、最主要的症状,在诊断标准中骨密度的诊断一直被公认为黄金标准。绝经后骨质疏松(PMOP)患者中所表现出中医特有的症状或证候是否与骨密度有关,能否可以作为PMOP早期诊断或判断骨量丢失程度的参考指标之一,这是本课题尝试探讨的问题之一。
此外,针对PMOP的治疗,现代医学多采用骨吸收抑制剂或骨形成促进剂等生化制剂,剂量难以控制,长期服用有一定的毒副作用,临床疗效也不显著。PMOP患者在骨折发生前,大量分散聚集在社区中,在社区开展相关临床研究有一定的示范意义。因此,我们在证候学研究的基础上,制定并完善一套具有中医特色的综合干预方案,在社区对患者进行示范性临床干预研究,以期减少患者痛苦、提高临床疗效,并对其疗效评价方法进行探索性研究。该研究具有一定的社会学意义以及推广价值。
1研究目的
探讨PMOP中医症状、中医证候与骨密度不同阶段之间的相关关系；在社区针对PMOP患者开展中医综合方案干预下的示范性研究,探索性采用发展模型和混合效应比例优势模型对综合方案进行疗效评价研究。
2研究方法
2.1在社区招募患者,共入组患者245例,采集相关临床数据,录入并建立数据库。采用卡方检验和有序Logistic回归,分析中医症状、中医证候与骨密度不同阶段之间的关系。
2.2采用前瞻性类试验研究设计,在社区开展治疗PMOP的临床研究。试验组(20例),对照组(20例)。试验组采用中医综合干预方案,方案包括中药免煎颗粒剂(淫羊藿、枸杞子、丹参),配合传统运动八段锦,以及乌骨鸡汤为主要原料的药膳进行协同治疗；对照组采用单一口服钙制剂(钙尔奇D600)。两组观察疗程均为6个月。疗效评价指标为视觉模拟疼痛评分(VAS)、中医症状及骨密度值。疗效评价方法：采用发展模型和混合效应比例优势模型。
3研究结果
3.1中医症状、中医证候与骨密度不同阶段的相关性研究结果
3.1.1将245例绝经后骨量异常的患者,按照骨密度的T值,分为骨量减少、骨质疏松、严重骨质疏松三个阶段。按照症状积分排序：腰膝酸软(598分)、骨痛(516分)、下肢拘挛(502分)、畏寒肢冷(474分)等症状积分较高。下肢拘挛与骨密度不同阶段存在一定关系,且有统计学差异(P<0.05)。腰膝酸软、骨痛、畏寒肢冷、健忘与骨密度不同阶段相关性没有统计学差异(P>0.05)。
3.1.2将245例患者的证候因素按照肾阳虚证、肾阴虚证、血瘀证进行分类。通过有序Logistic回归分析,结果显示三种证候因素与骨密度不同阶段存在相关关系,且有统计学差异(P<0.01)。肾阳虚患者各部位的骨密度值皆低于肾阴虚、血瘀证患者各部位的骨密度值,且有统计学差异(P<0.01)。在骨量减少阶段,患者以血瘀证居多(占76.6%)；在骨质疏松阶段,患者以肾阳虚(49.1%)与血瘀证(33.3%)居多,肾阴虚证(17.6%)较少；在严重骨质疏松阶段,患者以肾阳虚证居多(占80%),且有统计学差异(P<0.05)。
3.2中医综合干预方案的评价结果
3.2.1试验组相对对照组,VAS评分的平均结局分值有更多下降,额外下降的0.23分,有统计学差异(P<0.05)；中医症状积分的平均结局分值有更多下降,额外下降的0.78分,有统计学差异(P<0.05)。两组对下肢拘挛、畏寒肢冷、骨痛、腰膝酸软症状均有一定的缓解作用,但试验组更优于对照组,优于对照组的估计参数分别是0.55、0.40、0.32、0.25,具有统计学差异(P<0.05)；试验组对足跟痛、盗汗、少气懒言、健忘等症状有所改善,而对照组无改善,两组具有统计学差异(P<0.05)。
3.2.2对于减缓骨密度的下降,试验组疗效优于对照组,且有统计学差异(P<0.05)。对于腰椎骨密度的改善,试验组优于对照组,且有统计学差异(P<0.05)。对于股骨颈、股骨粗隆、大转子、Wards三角区骨密度的改善,虽然两组结果在统计学上没有差异(P>0.05),但是从描述统计中可以表明试验组患者的骨密度增长值相对较大,同时骨密度减少的患者也少于对照组,具有一定的临床意义。
4结论
4.1下肢拘挛与骨密度存在相关关系,可以作为早期诊断PMOP的参考指标之一。PMOP的不同证候与骨密度不同阶段之间存在着一定的相关性。骨量减少人群多表现为血瘀证,骨质疏松症或严重骨质疏松症人群多表现为肾阳虚证。患者的不同证候可以作为判断骨量丢失程度的参考指标之一。4.2在社区进行的临床研究,适宜采用前瞻性类试验的设计方法,中医综合干预方案对患者疼痛的缓解、症状的改善更优于单一钙剂的疗效,对延缓骨密度的下降,或提高部分受试者的骨密度值也有一定的疗效。
4.3发展模型和混合效应比例优势模型是适用于对临床试验重复测量数据进行疗效评价的统计学方法。
本研究将中医综合干预方案应用于PMOP治疗,并在社区开展前瞻性类试验,对临床试验重复测量数据采用发展模型和混合效应比例优势模型进行疗效评价,具有一定的创新性。
With the arrival of aging society, the ratio of postmenopausal osteoporosis(PMOP) increasing has become an urgent need to address global public health problems. The most serious complication of osteoporosis is fracture. The fracture incidence is far more than lung cancer, stroke and heart disease incidence, which bring the family and community serious health and economic pressure.
There are many researches show that the pain is the most common and the most important symptoms of PMOP. The diagnosis of bone mineral density(BMD) has been recognized as the gold standard of the diagnostic criteria. Are there any relationship between the symptoms and BMD; any relationship between syndromes and BMD, whether if it can be used as one of the early diagnosis or the determine reference which can judge the extent of bone loss.
Currently, the treatment for PMOP, bone resorption inhibitor and bone formation promoting are used in Modern Medicine. there are difficult to control the Dose of the Biological agents, even there are certain side effects with long-term use. Therefore based on the syndrome, we carry out a demonstration study of the integrated project in the community and exploratory the research on clinical effectiveness evaluation of PMOP with integrated project in TCM.
1 Objectives
Study the relationship which between symptoms of PMOP and bone mineral density; study the relationship which between syndromes of PMOP and bone mineral density. Carry out a demonstration study of the integrated project in the community and exploratory the research on clinical effectiveness evaluation of PMOP with integrated project in TCM based on the growth model and the mixed effects proportional odds model.
2 Methods
2.1 There are 245 patients were enrolled in the community,then we collected、inputed clinical datas and established databases. Using chi-square test and Logistic regression to observe the the relationship between clinical symptoms and bone mineral density; between syndromes and bone mineral density.
2.2 Design a prospective quasi-experimental which treat PMOP in the community. By SAS9.1.3 software, the ratio of the experimental group (20 cases) and control group (20 cases)is 1:1, the baseline of the two groups are consistent. Experimental group received an integrated project which include traditional chinese medicine、sports and diet; the control group received Caltrate D600. Two groups were observed for 6 months. Evaluation standards for the visual analog pain score (VAS), clinical symptoms and bone density. Clinical Evaluation Methods:the Growth model and mixed effects proportional odds model.
3 Resulets
3.1 clinical symptoms, syndromes associated with bone mineral density at different stages of research
3.1.1 245 cases of abnormal bone mass in postmenopausal patients, according to T-bone mineral density values were divided into three stages:bone loss, osteoporosis, severe osteoporosis. According to symptom scores:weak waist (598 points), pain (516 points), lower limb Spasm (502 points), aversion to cold (474 points), score higher. There is a certain relationshipat spasm and bone mineral density at different stages of lower limb, and there is significant difference (P<0.05). Waist and knee weakness, bone pain, aversion to cold, forgetfulness associated with different stages of bone mineral density was not statistically significant (P>0.05).
3.1.2 245 cases of patients with the syndrome factors in accordance with the deficiency, Kidney Yin Deficiency, blood.stasis syndrome was classified. Logistic regression analysis through the orderly, the results show that three kinds of syndromes and bone mineral density at different stages of factors correlated, with statistical difference (P <0.01). The bone mineral density values of Kidney yang deficiency patients is less than yin deficiency and blood stasis syndrome of bone mineral density in different parts, and there is significant difference (P<0.01). Patients with blood stasis are majority (76.6%) at bone loss stage; Patients with deficiency (49.1%) and blood stasis (33.3%) in kidney yin deficiency syndrome (17.6%) are less at osteoporosis stage; at severe osteoporosis stage, the majority of patients with kidney yang deficiency syndrome (80%), with statistical difference (P<0.05).
3.2 Traditional comprehensive intervention program evaluation results
3.2.1 Experimental group compared to control group, VAS scores decreased an average outcome scores more, and an additional drop of 0.23 points was significantly different (P<0.05); TCM symptom score, the average outcome score dropped more additional 0.78 points decline, with significant difference (P<0.05)., There is a certain relieve at spasm of the lower limb group, aversion to cold, bone pain, weak waist in the two groups, but the experimental group was better than the control group, the estimated parameters. better than the control group were 0.55,0.40,0.32,0.25 with significant difference (P<0.05); Experimental group on heel pain, night sweats, less gas lazy words, forgetfulness and other symptoms has improved, while the control group had no improvement, the two groups were statistically different (P<0.05).
3.2.2 For the slow decline in bone mineral density, experimental group was better than the control group, with statistical difference (P<0.05). For the lumbar spine bone mineral density improvement in the experimental group was better than the control group, with statistical difference (P <0.05). For the femoral neck, femoral trochanter, greater trochanter, Wards triangle bone mineral density improvement, although the two sets of results were not statistically different (P>0.05), but from the description that the test statistics can increase the value of bone mineral density in patients relatively large, while in patients with reduced bone mineral density than the control group also has some clinical significance.
4 Conclusions
4. IThere are the relationship between leg cramps and BMD, leg cramps can be the reference indicator of early diagnosis. There are a certain correlation between the different syndromes of PMOP and BMD. Most people of bone loss showed blood stasis syndrome, most people of osteoporosis or severe osteoporosis showed deficiency syndrome. Different Syndromes can be one of the reference indicator of degree of bone loss.
4.2 In the community, the forward-looking of quasi-experiment is an appropriate design method during the clinical trials;with the traditional comprehensive intervention program, the pain relief, the symptoms improvement of the patients are better than with only Calcium. Slow decline in bone mineral density, also and even improve bone density values also have a certain effect.
4.3 The growth model and the mixed effects proportional odds model is applicable to evaluate the clinical efficacy with repeated measurements data.
In this study, Innovation presence the treatment method of PMOP with the comprehensive intervention program; the conduct of the the forward-looking of quasi-experiment in the communities; the evaluate method of the repeated measurements data with the growth model and the mixed effects proportional odds model
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