It ought to be mentioned that by the end of the 7-12 months Extension period, patients were older and, thus, at higher fracture risk compared with the first 3?years of FREEDOM, potentially underestimating the fracture risk reduction observed with denosumab treatment in this longitudinal study without a parallel comparator arm. (Extension). Among placebo subjects who completed FREEDOM and enrolled in the Extension, wrist, forearm, humerus, and upper limb fracture rates and rate ratios between different time periods (FREEDOM years 1C3, Extension years 1C3, and Extension years 4C7) were computed. BMD at the ultradistal radius, 1/3 radius, and total radius was analyzed in a subset of subjects in a BMD substudy. Results This analysis included 2207 subjects (116 in the BMD substudy). Fracture rates decreased over the 7-12 months Extension; fracture rate ratios between Extension years NMS-873 4C7 (denosumab) and FREEDOM years 1C3 (placebo) reduced significantly for the wrist (0.57), forearm (0.57), humerus (0.42), and upper limb (0.52; values were not adjusted for multiplicity. Results Subjects Of the 3906 subjects randomized to placebo in FREEDOM, 2207 joined the FREEDOM Extension. The FREEDOM BMD substudy enrolled 441 subjects (209 placebo and 232 denosumab) at FREEDOM baseline; results from the FREEDOM substudy have previously been published [29]. Among the 209 placebo subjects in the FREEDOM BMD substudy, 116 enrolled in the Extension and experienced at least one 1/3 radius BMD measurement at baseline or postbaseline in the Extension. Baseline characteristics for FREEDOM and FREEDOM Extension subjects who entered FREEDOM Extension and those who participated in the BMD substudy are shown in Table ?Table1.1. At the beginning of the FREEDOM trial, subjects had a imply age of 72?years, 28% of the subjects were over the age of 75?years, and 22% had a prevalent vertebral fracture. Within the BMD substudy at FREEDOM baseline, mean age was 72?years, 34% of the subjects were over the age of 75?years, 21% had a prevalent vertebral fracture, and mean (standard deviation) BMD T-score was ??2.5 at the 1/3 radius and ??2.5 at the ultradistal radius. Table 1 FREEDOM and Extension baseline characteristics Fracture incidence (95% CI) per 100 subject-years at the a wrist, b forearm, c humerus, and d all upper limb. 95% CIs were estimated by NMS-873 generalized estimating equation (GEE) method in a Poisson regression model. All values were not adjusted for multiplicity. CI, confidence interval The incidence of wrist fractures was 1.02 per 100 subject-years during FREEDOM years 1C3 (during which all subjects received placebo) and 0.96 during Extension years 1C3 (during which all subjects received denosumab; rate ratio not significant), and decreased to 0.58 during Extension years 4C7 (rate ratio (95% CI)?=?0.57 (0.38C0.86); valuevalue /th /thead a. Ultradistal radiusFREEDOM (placebo)??12 months 1113??0.4 (??1.3, 0.6)0.4457N/AN/AN/A??12 months 2109??0.9 Rabbit polyclonal to AK5 (??1.9, 0.1)0.0633N/AN/AN/A??12 months 3111??2.1 (??3.5, ??0.8)0.0014N/AN/AN/AExtension (denosumab)??12 months 11130.6 (??1.1, 2.4)0.45411142.9 (1.2, 4.5)0.0008??12 months 21070.6 (??1.3, 2.4)0.53711082.8 (1.1, 4.5)0.0015??12 months 3731.2 (??0.6, 3.0)0.2055733.5 (1.7, 5.3)0.0001??12 months 5592.2 (0.4, 4.0)0.0195594.5 (2.8, 6.2) ?0.0001??12 months 7390.7 (??1.3, 2.7)0.4963393.2 (1.2, 5.3)0.0025b. 1/3 radiusFREEDOM (placebo)??12 months 1113??0.1 (??0.6, 0.5)0.7807N/AN/AN/A??12 months 2109??0.7 (??1.42, ??0.1)0.0275N/AN/AN/A??12 months 3111??1.2 (??1.9, ??0.4)0.0024N/AN/AN/AExtension (denosumab)??12 months 1113??1.0 (??1.7, ??0.3)0.00721140.3 (??0.2, 0.9)0.2308??12 months 2107??1.2 (??1.9, ??0.4)0.00331080.2 (??0.4, 0.9)0.5141??12 months 373??0.2 (??1.1, 0.7)0.6519731.3 (0.5, 2.0)0.0011??12 months 5590.3 (??0.7, 1.3)0.5451591.8 (0.9, 2.7)0.0001??12 months 7390.6 (??0.8, 2.1)0.3974392.2 (0.9, 3.6)0.0017c. Total radiusFREEDOM (placebo)??12 months NMS-873 1113??0.4 (??1.0, 0.2)0.1534N/AN/AN/A??12 months 2109??1.2 (??1.8, ??0.5)0.0003N/AN/AN/A??12 months 3111??1.9 (??2.6, ??1.2) ?0.0001N/AN/AN/AExtension (denosumab)??12 months 1113??1.0 (??1.7, ??0.2)0.01391141.2 (0.7, 1.8) ?0.0001??12 months 2107??1.2 (??2.0, ??0.3)0.00761081.1 (0.4, 1.7)0.0012??12 months 373??0.3 (??1.2, 0.5)0.4608732.0 (1.3, 2.8) ?0.0001??12 months 5590.1 (??0.8, 1.1)0.7928592.5 (1.7, 3.4) NMS-873 ?0.0001??12 months 739??0.4 (??1.7, 0.9)0.5693392.1 (0.9, 3.3)0.0009 Open in a separate window em n /em ?=?quantity of subjects with observed data Based on a repeated-measures mixed-effects model adjusted for treatment, age stratification variable, visit, baseline value, machine type, treatment-by-visit conversation, and baseline value-by-densitometry machine-type conversation em CI /em , confidence interval; em LS /em , least squares; em N/A /em , not applicable Open in a separate windows Fig. 2 Percentage switch in ultradistal radius, 1/3 radius, and total radius BMD from FREEDOM baseline. em n /em ?=?quantity of subjects with observed data. Percentage switch based on a repeated-measures mixed-effects model adjusted for treatment, age stratification variable, visit, baseline BMD value, machine type, treatment-by-visit conversation, and baseline value-by-machine-type conversation. * em p /em ? ?0.05 vs FREEDOM baseline. BMD, bone mineral density; BTM, bone turnover marker; CI, confidence interval; DXA, dual-energy x-ray absorptiometry; Q6M, every 6?months Discussion.
