BACKGROUND-Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.

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A B S T R A C T PurposeTo characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT). Patients and MethodsWe prospectively evaluated LBM in a prespecified substudy of a randomized controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) with a baseline and at least one on-study LBM assessment. Patients were stratified by age (Ͻ 70 v Ն 70 years) and by ADT duration (Յ 6 v Ͼ 6 months). ResultsMedian ADT duration was 20.4 months at study baseline. Mean LBM decreased significantly from baseline, by 1.0% at month 12 (95% CI, 0.4% to 1.5%; P Ͻ .001; n ϭ 248), by 2.1% at month 24 (95% CI, 1.5% to 2.7%; P Ͻ .001; n ϭ 205), and by 2.4% at month 36 (95% CI, 1.6% to 3.2%; P Ͻ .001; n ϭ 168). Men age Ն 70 years (n ϭ 127) had significantly greater changes in LBM at all measured time points than younger men. At 36 months, LBM decreased by 2.8% in men age Ն 70 years and by 0.9% in younger men (P ϭ .035). Men with Յ 6 months of ADT at study entry (n ϭ 36) had a greater rate of decrease in LBM compared with men who had received more than 6 months of ADT at study entry (3.7% v 2.0%; P ϭ .0645). ConclusionIn men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.

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Medical studies often collect physiological and/or psychological measurements over time from multiple subjects, to study dynamics such as circadian rhythms. Under the assumption that the expected response functions of all subjects are the same after shift and scale transformations, shape-invariant models have been applied to analyze this kind of data. The shift and scale parameters provide efficient and interpretable data summaries, while the common shape function is usually modeled nonparametrically, to provide flexibility. However, due to the deterministic nature of the shift and scale parameters, potential correlations within a subject are ignored. Furthermore, the shape of the common function may depend on other factors, such as disease. In this article, we propose shape-invariant mixed effects models. A second-stage model with fixed and random effects is used to model individual shift and scale parameters. A second-stage smoothing spline ANOVA model is used to study potential covariate effects on the common shape function. We apply our methods to a real data set to investigate disease effects on circadian rhythms of cortisol, a hormone that is affected by stress. We find that patients with Cushing's syndrome lost circadian rhythms and their 24-hour means were elevated to very high levels. Patients with major depression had the same circadian shape and phases as normal subjects. However, their 24-hour mean levels were elevated and amplitudes were dampened for some patients.