Subjects The 412 women enrolled in the parent phase 2 study were postmenopausal, ≤80 years old, and had a BMD T-score between −1.8 and −4.0 for the lumbar spine, or between −1.8 and −3.5 for either the total selleck inhibitor hip or femoral neck. The subjects who agreed to participate in the extension study had to have successfully completed the parent study, including the end-of-study visit at month 48. Subjects were excluded if, during the

parent study, they had experienced severe and/or serious adverse events or abnormal laboratory results thought to be related to denosumab; discontinued investigational product due to protocol-specified BMD decrease during the study; missed two or more scheduled administrations of investigational product during year 3 or 4; used any bone active drugs; or developed a disease known to affect bone metabolism. Efficacy outcomes Details of the assessment of BMD by dual-energy x-ray absorptiometry (DXA) and the collection and measurements of markers of bone turnover have been described previously [11, 12]. During the extension study, DXA scans of the lumbar spine, proximal femur,

and one-third radius were measured annually and were analyzed centrally. Serum bone turnover markers, C-telopeptide of type 1 collagen (CTX) and bone-specific alkaline phosphatase (BSAP), were collected after an overnight fast and before the next dose of denosumab at the extension study baseline (end of year 4 of the parent study), and at 6-monthly intervals throughout PD184352 (CI-1040) the study extension. Reports of adverse events were collected at each visit including information about new clinical fractures. Clinical PARP activation laboratory

measurements for safety assessment included standard hematology and serum chemistries that were performed at every visit in the study extension through month 24 (see more chemistry performed also at month 25 or month 1 of year 3) and at the final visit at month 48. A central laboratory, Covance Laboratories (Indianapolis, IN) was used to analyze all hematology and serum chemistry. Anti-denosumab binding antibody titers were drawn at entry, month 1, 6, and 12, and then yearly throughout the extension study. Antibody evaluation used a validated electrochemiluminescent immunoassay, and a cell-based assay was used to screen positive samples, as previously described [10–12]. Treatments Treatment groups in the parent study and the extension study are presented in Fig. 1. The 200 subjects in the extension study all received open-label denosumab 60 mg subcutaneously every 6 months (Q6M) with the last dose administered at month 42 of the extension study. Here, our efficacy findings focus on subjects who received 8 years of continued denosumab in the parent and extension studies, and those who received placebo for 4 years in the parent study followed by 4 years of denosumab in the extension study.