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

Abstract

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).

Keywords: Androgen-deprivation therapy; Bone mineral density; Prostate cancer; Transdermal oestradiol.

Fig. 1

PATCH trial schema. The allocation ratio was 1:2 for luteinising hormone-releasing hormone agonists (LHRHa) to oestradiol patches during the first stage of the trial (before February 21, 2011) to optimise the experience of the patches and 1:1 thereafter. Patients in the bone mineral density study were enrolled from seven of the participating sites between August 2006 and September 2012. PFS = progression-free survival.

Fig. 2

Flowchart of patients included in the analysis of change in lumbar spine bone mineral density at 1 yr from baseline (primary outcome measure). BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; LHRHa = luteinising hormone-releasing hormone agonists; LS = lumbar spine; OP = oestradiol patches. ^* The allocation ratio was 1:2 for LHRHa to OP before February 21, 2011, and 1:1 thereafter. ^$ The patch dose regimen was increased in August 2007 . ⁺ These patients contributed to at least one of the analyses on BMD change. ^{^} The main analysis of the primary outcome was restricted to patients with at least two evaluable LS vertebrae within L1–4 on both the baseline and 1-yr scans.

Fig. 3

Mean percentage change (95% confidence interval) in bone mineral density at 1 and 2 yr from baseline by treatment arms. (a) All patients; (b) patients still on allocated treatment only (ie, patients who were still on allocated treatment at the time of the scan with no additional anticancer therapy, with those on oestradiol patch with oestradiol values <250 pmol/l assumed not to be adhering to the patch regimen). The analyses at 1 and 2 yr are based on different numbers of patients (see Table 2, Table 3). LHRH = luteinising hormone-releasing hormone.