Allocation of participants Eight hundred thirty-seven potentially eligible women were invited to undergo the screening examinations. Among the 435 eligible cases, 431 cases were randomized into the isoflavone treatment group or the placebo group (Fig. 1). We obtained a randomization code for each participant using the permuted randomization method with a block size of eight within each center. For each center, random codes for

isoflavone or placebo were evenly generated. Each randomization number was assigned to an individual subject according to the time sequence of the subject becoming eligible. Each eligible case was randomized to one of the two treatment groups in a 1:1 ratio according to a randomization

list. An identification Epigenetics Compound Library supplier number was not re-allocated, if the subject was withdrawn from the study. Fig. 1 Enrollment flow chart of patients. Superscript a National Taiwan University Autophagy Compound Library Hospital is abbreviated as NTUH, Changhua Christian Hospital as CCH, and National Cheng Kung University Hospital as NCKUH. Superscript b AE denotes adverse events Study products Each isoflavone capsule contained 50 mg of isoflavones (aglycone equivalents) of which genistein and daidzein comprised 57.5% and 42.5%, respectively, as evidenced by high performance liquid chromatography (HPLC) analysis, and the other components were microcrystalline cellulose, xylitol, and caramel. Each subject in the isoflavone Cobimetinib clinical trial group took three capsules of isoflavones twice a day. The remaining subjects took three placebo capsules twice a day. Each placebo capsule contained microcrystalline cellulose, xylitol, caramel, and soybean sauce flavor without isoflavones. The net weight of the content inside each capsule

was 280 mg. The exterior of the isoflavone and placebo capsules appeared identical, and the capsules were distributed to each participant in a double-blind fashion. All participants also took a single calcium phosphate tablet, containing 300 mg of elemental calcium and 62.5 IU of vitamin D3 twice daily (Bio-cal®, TTY Co. Ltd, Taipei, Taiwan). Laboratory tests and questionnaires After an overnight fast, venous blood was sampled to determine HbA1c, plasma glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, high sensitivity C-reactive protein, urea nitrogen, creatinine, uric acid, ALT, and AST at baseline and 4, 48, and 96 weeks. Serum bone-specific alkaline phosphatase (BAP, Beckman Access Ostase®, Fullerton, CA, USA; interassay coefficient of variation (CV) = 14% and intraassay CV = 9%) and urine collected for routine urinalysis and N-telopeptide of type 1 collagen (NTx, Vitros Immunodiagnostic Products, Ortho-Clinical Diagnostics, Buckinghamshire, UK; interassay CV = 15% and intraassay CV = 10%) were examined at baseline and 48 and 96 weeks.