A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol.

BACKGROUND: Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. OBJECTIVE: To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). DESIGN, SETTING, AND PARTICIPANTS: Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006-2011; 1:1, thereafter) were recruited into a BMD study (2006-2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. INTERVENTIONS: LHRHa as per local practice, OP (FemSeven 100µg/24h patches). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. RESULTS AND LIMITATIONS: A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was -0.021g/cm(3) for patients randomised to the LHRHa arm (mean percentage change -1.4%) and +0.069g/cm(3) for the OP arm (+6.0%; p<0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa -3.0% and OP +7.9% (p<0.001). CONCLUSIONS: Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. PATIENT SUMMARY: This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial. TRIAL REGISTRATION: ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).

alpha,beta-MeATP augments the UTP contraction of rabbit basilar artery.

The mechanism underlying the interaction between alpha,beta-methyleneadenosine 5'-triphosphate (alpha,beta-MeATP) and uridine 5'-triphosphate (UTP) was investigated using the basilar artery of a rabbit. UTP induced a concentration-dependent contraction, whereas P2X receptor agonists, such as alpha,beta-MeATP and 2-methylthioadenosine 5'-triphosphate (2-MeSATP), did not induce any contraction up to 100 microM. alpha,beta-MeATP augmented the UTP contraction two-fold, immediately and reversibly. This effect was observed with ectonucleotidase inhibition with 1 mM Ni(2+), the removal of extracellular Ca(2+) or Evans blue. The contractile response to adenosine 5'-O-(3-triphosphate) (ATPgammaS), a selective agonist for P2Y(4), was augmented by pretreatment with alpha,beta-MeATP also. ATPgammaS had no additional effect on the UTP contraction fully activated with alpha,beta-MeATP. UTP (100 microM) did not induce an increase in cytosolic Ca(2+) in a rabbit basilar arterial strip; however, in the presence of 1 mM alpha,beta-MeATP, UTP induced a significant increase in cytosolic Ca(2+). These results suggest that alpha,beta-MeATP facilitates the activation by UTP of the P2Y receptor (P2Y(4)) of the rabbit basilar artery through mechanisms other than nucleotidase inhibition, and that it does not do so via a P2X receptor.