Building Of Pharmacodynamic Models Of Postmenopausal Osteoporosis For The Clinical Evaluation Of Traditional Chinese Medicines

Postmenopausal osteoporosis is an impactful public health issue.Though there are many available anti-osteoporosis drugs for clinical therapy which are recommended by treatment guidelines,the quantitative effect of these drugs are still unclear.Furthermore,the dosage of universal basic treatment such as calcium supplementation was in dispute among different guidelines.The clinical decisions are often made based on empirical evidences,which hard to reach the aim of precision medicine and national administration.Unfortunately,the same situation is occuered in Traditional Chinese Medicines?TCMs?.This aritcle was a methodology research,in which pharmacodynamics models were developed based on antiresorptive agents as modeling tool.Simulation and prediction was performed using the established tool to quantitatively evaluate the efficacy of TCMs.Ultimately,this study will provide referable methodology for similar clinical trial and guide their design.The chapter 1 of this study regards the difference of bone mineral density?BMD?change from baseline between treatment group and controlled group as the evaluation index,and developed an E_max model with two impact factors?age and dosage?to describe the time course of BMD increase.By modeling and simulation,this study confirmed efficacy of calcium intake,answered the international dose-response question and established referable criterion for judging the effectiveness of a new drug.The well-fitted model proved the feasibility for modeling method to solve clinical problems in osteoporosis treatment and provide reliable and valuable information for clinical therapy and clinical trial design.While this part of study has solved some essential clinical problems,the limitation of BMD was investigated by devopled modeling methology.By reason of slow bone disease progression and insensitive BMD response,it often takes more than 2 years for clinical trials to observe a statistically significant endpoint,and it is not worth to take the risk and cost time and expense for negative results.Once BMD response is able to be predicted via BTMs response,clinical decision-making based on BMD response may be more efficiently enabling optimal trial design for a targeted BMD outcome.The chapter 2&3 of this study involved the frequently-used antiresorptive agents and found out the asynchronous relationship between BTMs and BMD in lumbar spine?LS?and total hip?TH?.Fisrtly the pharmacodynamics of BTMs were described by exponential onset models based on disease progression and placebo effect.The semi-mechanistic model consists of dynamic resorption-formation part and linear mineralization part based on bone metabolic mechanism was then developed to describe the dynamic process in bone remodeling.Validated externally by data of 8long-term extension studies and additional data of Raloxifene,developed models were proved to be reliable and reusable for quantitative prediction of BMD increase.The gained model can predict long-term BMD response by short-term BTMs and can be reused in drugs with the same mechanism of action.Taking the advantage of prediction function,the key decisions for promoting clinical trials from phase I to II&III can be made earlier.In addition,this study also summarizes the efficacy framework of first-line drugs and expounds quantitative effect of placebo and basic therapy in a mechanism perspective.The current antiresorptive agents perform high efficacy,however,poor compliance and severe toxicity limit their clinical application.In this extent,TCMs are pontential drug to be developed.However,the efficacy of TCM is ambiguity and researchers can hardly gain significant endpoint due to short trial duration.Therefore,the chapter 4 of this study utilizes the similarity in mechanism of action between antiresorptive agents and TCM,and applies established predictive model in TCM.The BTMs inhibition outcome of included TCMs was lower than first-line antiosteoporosis agents commonly used in clinical,which indicates adverse effects caused by exclusive suppression of bone resorption may occur infrequently in TCMs treated postmenopausal patients.By using short-term clinical data of Qing'e Formula,Bushenhuoxue Formula and Qianggu Yin,the estabilished model predicts and evaluates their corresponding long-tern BMD.The modeling results indicated that lumbar BMD pharmacodynamics characteristics of three TCMs are similar with each other and perform equivalence to that of antirespotive drug Risedronate after 2 years,but the onset rate is relatively slower.Supported by simulation result,it takes at least 1.5 years for non-inferiority clinical trials of TCMs to attach a positive outcome.