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Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.
Ren, Z, Xu, J, Bai, Y, Xu, A, Cang, S, Du, C, Li, Q, Lu, Y, Chen, Y, Guo, Y, et al
The Lancet. Oncology. 2021;(7):977-990
Abstract
BACKGROUND China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING Innovent Biologics. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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Comparison of Quality of Life and Nutritional Status of Between Roux-en-Y and Billroth-I Reconstruction After Distal Gastrectomy: A Systematic Review and Meta-Analysis.
Du, N, Chen, M, Shen, Z, Li, S, Chen, P, Khadaroo, PA, Mao, D, Gu, L
Nutrition and cancer. 2020;(5):849-857
Abstract
Background: This paper purports to use a meta-analysis to compare the postoperative quality of life (QoL) and nutritional status of between Roux-en-Y (R-Y) and Billroth-I (B-I) reconstruction after distal gastrectomy.Methods: For this study, the following databases were searched for articles published from inception until December 2018: PubMed, Web of Science, EBSCO, and Cochrane library.Results: A total of 13 eligible studies, covering 3645 patients, were selected for a meta-analysis. The analysis showed that compared with B-I group in term of short-term outcomes, patients undergoing R-Y reconstruction did not only have significantly better physiological function (P = 0.02), but had significantly less pain (P = 0.04). In the long-term outcomes, the dyspnea and constipation in the B-I group were worse than that in the R-Y group (P = 0.004; P = 0.04, respectively). Patients in the B-I group had higher cholesterol than those in the R-Y group at 5 years postoperatively (P = 0.003). There were no significant differences in termof other nutritional indicators including total protein, cholesterol, albumin, hemoglobin and weight in short-term outcomes.Conclusions: The final conclusion was that R-Y may be superior to the B-I reconstruction in some aspects of QoL. Besides, R-Y reconstruction could reduce the patient's cholesterol level for a long time. For the short-term outcomes, there were no significant differences in other common nutritional indicators.
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CHA2DS2-VASc and SAMe-TT2R2 scores as predictors of recurrence for nonvalvular atrial fibrillation patients on vitamin K antagonists after radiofrequency catheter ablation.
Zhao, J, Zhou, D, Chen, M, Zhuo, C, Lin, Z, Zheng, L, Wang, Q
Journal of cardiovascular medicine (Hagerstown, Md.). 2020;(3):200-208
Abstract
AIMS: Atrial fibrillation is the most common sustained arrhythmia in the general population, and circumferential pulmonary vein isolation has emerged as a cornerstone in the treatment of drug-resistant atrial fibrillation. However, there is a paucity of data regarding the CHA2DS2-VASc and SAMe-TT2R2 scores as predictors of outcomes among patients with nonvalvular atrial fibrillation on vitamin K antagonists after radiofrequency catheter ablation (RFCA). METHODS The current prospective observational study enrolled 304 consecutive patients with atrial fibrillation who underwent RFCA. Warfarin was maintained for at least 3 months after RFCA. The 1-year atrial fibrillation recurrence rate was documented. RESULTS Persistent atrial fibrillation (P = 0.003), heart failure (P < 0.001), an enlarged left atrium (P = 0.003), current smoking (P < 0.001), the CHA2DS2-VASc score (P = 0.001), and the SAMe-TT2R2 score (P < 0.001) were univariate associated with recurrent atrial fibrillation. Cutoff analysis showed that a CHA2DS2-VASc score at least 3 (areas under the curve = 0.612; 95% confidence interval 0.537-0.687) and a SAMe-TT2R2 score at least 5 (areas under the curve = 0.642, 95% confidence interval 0.575-0.708) had the highest predictive value for atrial fibrillation recurrence. Patients with a CHA2DS2-VASc score at least 3 (P < 0.001) and a SAMe-TT2R2 score at least 5 (P = 0.001) had a higher probability of experiencing atrial fibrillation recurrence after RFCA compared with patients with a CHA2DS2-VASc score less than 3 and a SAMe-TT2R2 score less than 5. CONCLUSION CHA2DS2-VASc and SAMe-TT2R2 scores were associated with 1-year recurrence of atrial fibrillation in patients on vitamin K antagonists after RFCA. For CHA2DS2-VASc and SAMe-TT2R2 scores, a cutoff value of at least 3 and at least 5 had the highest predictive value for atrial fibrillation recurrence, respectively.
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Effect of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Biomarkers of Smoke Exposure: A Randomized Clinical Trial.
Hatsukami, DK, Luo, X, Jensen, JA, al'Absi, M, Allen, SS, Carmella, SG, Chen, M, Cinciripini, PM, Denlinger-Apte, R, Drobes, DJ, et al
JAMA. 2018;(9):880-891
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IMPORTANCE The optimal temporal approach for reducing nicotine to minimally or nonaddictive levels in all cigarettes sold in the United States has not been determined. OBJECTIVES To determine the effects of immediate vs gradual reduction in nicotine content to very low levels and as compared with usual nicotine level cigarettes on biomarkers of toxicant exposure. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, parallel-design study with 2 weeks of baseline smoking and 20 weeks of intervention was conducted at 10 US sites. A volunteer sample of daily smokers with no intention to quit within 30 days was recruited between July 2014 and September 2016, with the last follow-up completed in March 2017. INTERVENTIONS (1) Immediate reduction to 0.4 mg of nicotine per gram of tobacco cigarettes; (2) gradual reduction from 15.5 mg to 0.4 mg of nicotine per gram of tobacco cigarettes with 5 monthly dose changes; or (3) maintenance on 15.5 mg of nicotine per gram of tobacco cigarettes. MAIN OUTCOMES AND MEASURES Between-group differences in 3 co-primary biomarkers of smoke toxicant exposure: breath carbon monoxide (CO), urine 3-hydroxypropylmercapturic acid (3-HPMA, metabolite of acrolein), and urine phenanthrene tetraol (PheT, indicator of polycyclic aromatic hydrocarbons) calculated as area under the concentration-time curve over the 20 weeks of intervention. RESULTS Among 1250 randomized participants (mean age, 45 years; 549 women [44%]; 958 [77%] completed the trial), significantly lower levels of exposure were observed in the immediate vs gradual reduction group for CO (mean difference, -4.06 parts per million [ppm] [95% CI, -4.89 to -3.23]; P < .0055), 3-HPMA (ratio of geometric means, 0.83 [95% CI, 0.77 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.88 [95% CI, 0.83 to 0.93]; P < .0055). Significantly lower levels of exposure were observed in the immediate reduction vs control group for CO (mean difference, -3.38 [95% CI, -4.40 to -2.36]; P < .0055), 3-HPMA (ratio of geometric means, 0.81 [95% CI, 0.75 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.86 [95% CI, 0.81 to 0.92]; P < .0055). No significant differences were observed between the gradual reduction vs control groups for CO (mean difference, 0.68 [95% CI, -0.31 to 1.67]; P = .18), 3-HPMA (ratio of geometric means, 0.98 [95% CI, 0.91 to 1.06]; P = .64), and PheT (ratio of geometric means, 0.98 [95% CI, 0.92 to 1.04]; P = .52). CONCLUSIONS AND RELEVANCE Among smokers, immediate reduction of nicotine in cigarettes led to significantly greater decreases in biomarkers of smoke exposure across time compared with gradual reduction or a control group, with no significant differences between gradual reduction and control. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02139930.
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Comparative effectiveness of sodium-glucose co-transporter 2 inhibitors for controlling hyperglycaemia in patients with type 2 diabetes: protocol for a systematic review and network meta-analysis.
Chen, M, Xie, CG, Gao, H, Zheng, H, Chen, Q, Fang, JQ
BMJ open. 2016;(1):e010252
Abstract
INTRODUCTION As a new class of glucose-lowering drugs, sodium-glucose co-transporter 2 (SGLT2) inhibitors are effective for controlling hyperglycaemia, however, the relative effectiveness and safety of 6 recently available SGLT2 inhibitors have rarely been studied. Therefore, we aim to perform pairwise comparisons of the 6 SGLT2 inhibitors. METHODS AND ANALYSIS A systematic review and network meta-analysis will be conducted. Clinical studies that examine effectiveness and safety of either canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, tofogliflozin or luseogliflozin will be included. These studies will be systematically retrieved in MEDLINE, EMBASE and the Cochrane Library, from inception to November 2015. Two reviewers will independently screen for eligible studies and then extract data from the studies as well as assess risk of bias. Discrepancies in screening and data extraction will be arbitrated by a third reviewer. A traditional meta-analysis will be performed to combine the effect sizes calculated from head-to-head comparisons with a random effect model. The effect sizes computed from indirect comparisons will be further combined in a network meta-analysis. Heterogeneity will be tested with the Cochrane's Q statistic, and publication bias will be assessed using a funnel plot and the Egger's test. ETHICS AND DISSEMINATION Relative effectiveness and harms of the 6 SGLT2 inhibitors will be demonstrated through this systematic review and network meta-analysis. The result of the review will be disseminated through a peer-review journal and conference presentations. Patients, clinicians and policymakers will benefit from this review in selecting a SGLT2 inhibitor for glucose control in patients with type 2 diabetes. TRIAL REGISTRATION NUMBER PROSPERO CRD42015025981.
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Safety and effectiveness evaluation of a domestic peritoneal dialysis fluid packed in non-PVC bags: study protocol for a randomized controlled trial.
Zhou, J, Cao, X, Lin, H, Ni, Z, He, Y, Chen, M, Zheng, H, Chen, X
Trials. 2015;:592
Abstract
BACKGROUND Peritoneal dialysis is an important type of renal replacement therapy for uremic patients. In peritoneal dialysis, fluids fill in and flow out of the abdominal cavity three to five times per day. Usually, the fluid is packed in a polyvinyl chloride (PVC) bag. Safety concerns have arisen over di-(2-ethylhexyl) phthalate, which is essential in the formation of PVC materials. In 2011, the National Development and Reform Commission of China released a catalog of industrial structural adjustments, mandating the elimination of PVC bags for intravenous infusion and food containers. Although bags for peritoneal dialysis fluid were not included in the elimination list, several manufacturers began to develop new materials for fluid bags. HUAREN peritoneal dialysis fluid consists of the same electrolytes and buffer agent as in Baxter fluid, but is packed in bags that do not contain PVC. This multicenter randomized controlled trial was designed to compare peritoneal dialysis fluid packed in non-PVC-containing and PVC-containing bags. Further, the study sought to determine the proper dose of peritoneal dialysis fluid and the actual survival rates of Chinese patients undergoing peritoneal dialysis. METHODS/DESIGN The study participants are adults undergoing continuous ambulatory peritoneal dialysis for 30 days to 6 months. All eligible patients are randomized (1:1) to peritoneal dialysis with Baxter and HUAREN dialysis fluids (initial dose, 6 l/day), with dosages adjusted according to a unified protocol. The primary outcomes are the 1-, 2-, 3-, 4-, and 5-year overall survival rates. Secondary outcome measures include technique survival rates, reductions in estimated glomerular filtration rate, nutritional status, quality of life, cardiovascular events, medical costs and drop-out rates. Safety outcome measures include adverse events, changes in vital signs and laboratory parameters, peritonitis, allergies, and quality of products. DISCUSSION This study is the first to evaluate the long-term safety and effectiveness of a non-PVC packed peritoneal dialysis fluid. The effects of plasticizer on patient long-term survival will be determined. The characteristics of Chinese patients undergoing peritoneal dialysis will be determined, including proper dose, technique survival rates, patient survival rates, and medical costs. TRIAL REGISTRATION Clinicaltrials.gov NCT01779557 .
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Comparison of clinical features in patients with persistent and nonpersistent cryptococcal meningitis: twelve years of clinical experience in four centers in China.
Xu, XG, Pan, WH, Bi, XL, Fang, W, Chen, M, Zhu, Y, Zhou, J, Zhou, N, Pan, B, Li, M, et al
CNS neuroscience & therapeutics. 2013;(8):625-31
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BACKGROUND AND AIMS Cryptococcal meningitis (CM) has gradually increased in the recent 20 years in the whole world. Although the mortality decreased significantly in recent years, it was still high, especially in patients with persistent infection. Therefore, we compare differences of clinical features between persistent and nonpersistent CM patients. METHODS We conducted a retrospective review of medical records of patients diagnosed with CM from January 2000 to December 2011 in four centers in China, including demographic features, underlying diseases, clinical presentations, laboratory data, and so on. RESULTS Of 106 CM patients enrolled, 16 were identified as persistent cases. Among all variables, persistent CM patients were more like to be human immunodeficiency viruses (HIV) infection (P < 0.05), stiff neck (P < 0.01), a serum hemoglobin < 90 g/L (P < 0.01), a serum potassium concentration <2.7 mg/L (P < 0.01), an intracranial pressure (ICP) >400 mmH2 O (P < 0.01), and a latex agglutination cryptococcal antigen titer of cerebrospinal fluid (CSF LACT) >1:1024 (P < 0.01) than nonpersistent ones. A multivariate analysis showed that HIV infection (OR 7.49), stiff neck (OR 11.7), a serum potassium <2.7 mmol/L (OR 9.45), and an ICP >400 mmH2 O (OR 6.83) were closely correlated with persistent CM. CONCLUSIONS Although it is difficult to deal with persistent CM nowadays, some cases could be predicted early enough in the future, so as to be treated appropriately and have relatively good outcomes.
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Acute effects of nicardipine and esmolol on the cardiac cycle, intracardiac hemodynamic and endothelial shear stress in patients with unstable angina pectoris and moderate coronary stenosis: results from single center, randomized study.
Chen, SL, Hu, ZY, Zhang, JJ, Ye, F, Kan, J, Xu, T, Liu, ZZ, Zhang, YJ, Zhang, JX, Chen, M
Cardiovascular therapeutics. 2012;(3):162-71
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OBJECTIVE This study aimed to compare the acute effects of nicardipine and esmolol on hemodynamic and endothelial shear stress (ESS) in patients with unstable angina (UA) and moderate coronary stenosis (MCS). BACKGROUND Nicardipine and esmolol exhibit cardioprotection via different mechanisms. However, their acute effects on hemodynamic and ESS are still unknown. METHODS One-hundred sixteen patients with UA and MSC were randomly divided into nicardipine (n = 59) and esmolol (n = 57) groups. Drugs were injected as a bolus followed by continuous infusion to achieve the steady states defined as the mean blood pressure (MBP) reduced by ≥ 10% or a heart-rate change by ≥ 15 bpm, lasting for at least 10 min. The aortic pressure (AP), EKG, blood velocity, right atrial pressure, distal coronary pressure (DCP), systolic time (ST), isovolumetric diastolic time (IVDT), speed filling time (SFT), and ESS were simultaneously calculated at baseline and steady states. RESULTS Both drugs significantly reduced blood pressure and rate-pressure load. Infusion of nicardipine was associated with negative remodeling of the distal segment (P= 0.005). Esmolol, rather than nicardipine, increased minimal lumen diameter (P= 0.040), prolonged SFT (0.34 ± 0.03 s vs. 0.41 ± 0.03 s, P < 0.001), reduced DCP (P < 0.001) and increased blood velocity (33.65 ± 1.07 cm/s vs. 43.36 ± 1.25 cm/s, P < 0.001) at SFT stages, with increased blood-flow (P < 0.001). Both drugs increased downstream ESS. Esmolol significantly reversed abnormally increased ESS (P < 0.001) and increased upstream ESS compared with nicardipine (P < 0.001). CONCLUSION Beyond a similar reduction of AP, patients with UA and MCS could benefit more from the reduction of heart rate induced by esmolol (ChiCTR-TRC-10000964).
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The design and protocol of heat-sensitive moxibustion for knee osteoarthritis: a multicenter randomized controlled trial on the rules of selecting moxibustion location.
Chen, R, Chen, M, Kang, M, Xiong, J, Chi, Z, Zhang, B, Fu, Y
BMC complementary and alternative medicine. 2010;:32
Abstract
BACKGROUND Knee osteoarthritis is a major cause of pain and functional limitation. Complementary and alternative medical approaches have been employed to relieve symptoms and to avoid the side effects of conventional medication. Moxibustion has been widely used to treat patients with knee osteoarthritis. Our past researches suggested heat-sensitive moxibustion might be superior to the conventional moxibustion. Our objective is to investigate the effectiveness of heat-sensitive moxibustion compared with conventional moxibustion or conventional drug treatment. METHODS This study consists of a multi-centre (four centers in China), randomised, controlled trial with three parallel arms (A: heat-sensitive moxibustion; B: conventional moxibustion; C: conventional drug group). The moxibustion locations are different from A and B. Group A selects heat-sensitization acupoint from the region consisting of Yin Lingquan(SP9), Yang Lingquan(GB34), Liang Qiu(ST34), and Xue Hai (SP10). Meanwhile, fixed acupoints are used in group B, that is Xi Yan (EX-LE5) and He Ding (EX-LE2). The conventional drug group treats with intra-articular Sodium Hyaluronate injection. The outcome measures above will be assessed before the treatment, the 30 days of the last moxibustion session and 6 months after the last moxibustion session. DISCUSSION This trial will utilize high quality trial methodologies in accordance with CONSORT guidelines. It will provide evidence for the effectiveness of moxibustion as a treatment for moderate and severe knee osteoarthritis. Moreover, the result will clarify the rules of heat-sensitive moxibustion location to improve the therapeutic effect with suspended moxibustion, and propose a new concept and a new theory of moxibustion to guide clinical practices. TRIAL REGISTRATION The trial is registered at Controlled Clinical Trials: ChiCTR-TRC-00000600.
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Additive effect of alfacalcidol on bone mineral density of the lumbar spine in Taiwanese postmenopausal women treated with hormone replacement therapy and calcium supplementation: a randomized 2-year study.
Chen, M, Chow, SN
Clinical endocrinology. 2001;(2):253-8
Abstract
OBJECTIVE To evaluate the effect of 1alpha-hydroxyvitamin D3 on bone mineral density of the lumbar spine in postmenopausal women receiving hormone replacement therapy and calcium supplement. DESIGN A randomized, prospective 2-year clinical trial. PATIENTS AND MEASUREMENTS A total of 240 postmenopausal women were enrolled with randomized assignment of 120 patients to each treatment group (the D + E group of 1alpha-hydroxyvitamin D3 + sequential combined HRT + calcium supplement; the E group: sequential combined HRT + calcium supplement). None of the patients had received HRT for menopausal syndrome or osteoporosis before being enrolled in our study. Serum biochemical assays, electrolytes and calcitonin were performed at baseline and after 6 and 12 months of treatment. Bone mineral density (BMD) of L2-L4 was measured by dual energy X-ray absorptiometry (DXA) at the initial assessment and after 12 and 24 months of treatment. RESULTS One hundred and five patients (87.5%) in the D + E group and 92 patients (76.7%) in the E group completed the first 1-year study. Ninety-six patients (80%) in the D + E group and 80 patients (66.7%) in the E group completed the 2-year trial. Renal function, liver function, electrolytes and calcitonin showed no significant changes during the first year of follow-up. In the D + E group, the BMD of L2-4 increased 3.24 +/- 0.32% from baseline after 1 year (P < 0.05) and 5.32 +/- 0.23% after 2 years of treatment (P < 0.05). On the other hand, the changes of BMD in the E group were 1.12 +/- 0.34% after 1 year (P < 0.05) and 2.42 +/- 0.26% after 2 years of treatment (P < 0.05). The changes of BMD of L2-L4 of the D + E group were higher than the changes of the E group after both 1 and 2 years of treatment (P < 0.05). CONCLUSIONS Our study demonstrated that combination of 1alpha-hydroxyvitamin D3 with HRT is superior to HRT alone for the preservation of bone mineral density in postmenopausal women under calcium supplementation.