2011;77:1166C71. Epibrassinolide systemically-active hormonal providers such as abiraterone acetate and enzalutamide have each been shown to improve skeletal morbidity in specific medical situations. Denosumab is the only agent that has been shown to prevent osteoporotic fractures in males receiving androgen deprivation therapy and at elevated risk for fracture. It has also demonstrated superiority to the potent bisphosphonate zoledronic acid for the prevention of skeletal-related events in males with castration-resistant prostate malignancy metastatic to bone. Effectiveness and toxicity data will become discussed. 1.0% loss; 0.001) and a lower incidence of fresh vertebral fractures at 36 months (1.5% 3.9%; relative risk 0.38; 95% CI 0.19C0.78; = 0.006). Toremifene and raloxifene are selective estrogen receptor modulators that have been analyzed in males receiving ADT for prostate malignancy. Each has been shown to improve BMD,32,33 and toremifene offers been shown in a large phase III study to reduce fracture risk.47 One prominent adverse effect of toremifene was the observation of more frequent venous thromboembolic events (2.6% with toremifene 1.1% with placebo). Neither agent is definitely approved for use in males with prostate malignancy. Given the availability of these providers and the data supporting their use in males with prostate malignancy, testing and selection of treatment candidates is essential. Supplementation of calcium and vitamin D in all males receiving ADT is recommended by current National Comprehensive Tumor Network guidelines. A subset of those males will have risk adequate to justify pharmacologic therapy. Appropriate candidates for therapy should be recognized by predictive models that take medical factors beyond BMD into account. The World Health Corporation fracture risk assessment model FRAX (http://www.shef.ac.uk/FRAX/) is one such model. Clinical inputs include gender, age, height, weight, history of fracture, parental history of hip fracture, smoking status, use Epibrassinolide of glucocorticoids, daily usage of at least 3 devices of alcohol, rheumatoid arthritis and other causes of secondary osteoporosis. National Osteoporosis Foundation recommendations recommend the use of drug therapy to reduce fracture risk if 10 yr risk exceeds either of two thresholds ( 20% risk of major osteoporotic fracture or 3% risk of hip fracture).48 Synthesis ADT causes loss of BMD and is associated with an increased incidence of osteoporotic fracture. Osteoporosis consequently merits screening and management among males who receive ADT for prostate malignancy. Measurement of BMD can aid risk assessment, but is not properly sensitive in the absence of medical factors. The online World Health Corporation/FRAX fracture risk assessment tool is definitely one method of more comprehensive risk assessment and is recommended by National Comprehensive Cancer Network recommendations. For those who merit treatment, denosumab is the only approved agent that is supported by level 1 evidence of fracture prevention. Several bisphosphonates have been shown to improve BMD and are also sensible choices among treatment candidates. CASTRATION-RESISTANT NONMETASTATIC PROSTATE Tumor The natural history of advanced prostate malignancy strongly features risk for metastases to bone. Recent phase III tests of systemic providers in males with metastatic CRPC have enrolled populations with 80%C90% baseline prevalence of bone metastases.49,50,51 This propensity for the disease to metastasize to bone has led to efforts to prevent bone metastases in men who have not yet developed. Denosumab is the only agent that has been shown to delay the onset of bone metastases. No bone-targeted agent has been approved for the prevention of bone metastases. Observe Table 2 for a summary of data related to osteoclast inhibition in males with prostate malignancy. Table 2 Osteoclast-targeted therapy for males with prostate malignancy Open in a separate window Bisphosphonates have failed to demonstrate benefit for the prevention of bone metastases. Clodronate is definitely a relatively fragile bisphosphonate that was analyzed inside a well-designed phase III trial that did not demonstrate a significant difference relative to placebo in time to 1st bone metastasis.52,53 Zoledronic acid is more potent and was the subject of a phase III trial that closed early due to poor accrual and a lower than expected rate of bone metastases.54 Analysis of the placebo group of that trial revealed that time to first metastasis was shorter in men with prostate-specific antigen (PSA) 10 ng ml?1 (relative risk (RR) 3.18) and elevated PSA velocity (RR 4.34 for each 0.01 increase in PSA velocity).54 Denosumab was then examined inside a Epibrassinolide randomized phase FGF-18 III trial that met its primary endpoint, but did not led to authorization of the agent for this indication. The trial enrolled 1432 males with CRPC not metastatic to bone who have been at elevated risk for bone metastases as indicated by short PSA doubling time (10.0 months) and/or an absolute PSA value 8.0 ng dl? 1. They were randomized 1: 1 to receive denosumab (120.