Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications


Contemporary medical androgen deprivation therapy (ADT) to suppress testosterone for men with prostate cancer is achieved using LHRH agonists (LHRHa). This results, however, not only in reduced testosterone levels (by ∼95%) but also reduced endogenous oestrogen levels (by ∼80%); testosterone is the substrate for oestrogen through aromatization [1]. The use of LHRHa has increased such that it is now being employed progressively earlier during the natural history of the disease and for longer periods, often exceeding 10 years [2]; however, as a result of the loss of both male and female sex hormones, men on such long-term LHRHa also experience ‘castration syndrome’, a constellation of adverse events encompassing both a menopause and an analogous ‘andropause’, and can thereby develop serious toxicity including skeletal-related events (SKEs) such as osteoporosis and bone fracture. Shao et al. [3] add to the accumulating data concerning SKEs in this scenario. Their study identified men from a large population-based cohort with a diagnosis of localized prostate cancer (n = 75 994) who had increased pre-existing risk of SKEs at the time of diagnosis. Should such men subsequently be treated with LHRHa, as their risk of SKEs would be expected to be correspondingly higher? Is there a way to achieve medical castration whilst at the same time avoiding SKEs?

Before LHRHa therapy, oral oestrogen was one of the main therapeutic options for treating prostate cancer. Use as first-line therapy was discontinued in the 1980s, as studies showed that men treated with oral oestrogen had cardiovascular toxicity [4], thought to be a direct result of hepatic first-pass of oestrogen-inducing pro-coagulant proteins. More recent research suggests that parenteral administration of oestrogen appears to circumvent this cardiovascular toxicity by avoiding hepatic first-pass metabolism [5-7]. Additionally, there is a benefit (through exogenous oestrogen replacement) of maintaining endogenous levels of oestrogen, potentially avoiding menopausal symptoms. Oestrogen is inexpensive compared with contemporary ADT (LHRHa) and, as a single therapy, not only treats the cancer (suppressing testosterone to castrate levels) but also replaces lost endogenous oestrogen (thereby avoiding some of the adverse events of LHRHa). Oestrogen is known to inhibit osteoclastogenesis and increase osteoclast apoptosis, thereby suppressing bone resorption. These effects have been studied extensively in the context of the female menopause [8].

In a previous small study of men (n = 20) treated with transdermal oestradiol patches for newly diagnosed locally advanced or metastatic prostate cancer, of 12 baseline osteoporotic/osteopenic regions (in five patients), four showed improvement based on the WHO grading after a year of therapy and bone mineral density increased at all measured sites over time [9]. In another, much larger, study (n = 910) with long follow-up (∼9 years), no patient on parenteral oestrogen (i.m. polyestradiol phosphate) developed serious SKEs compared with 18 on combined ADT (anti-androgen with either LHRHa or bilateral orchidectomy) [6].

The Medical Research Council phase II randomized clinical trial, PATCH (Prostate Adenocarcinoma TransCutaneous Hormones), is comparing LHRHa with transdermal oestrogen patches in men with locally advanced or metastatic prostate cancer. In the first stage of this study (n = 254), similar rates of significant cardiovascular events (the primary outcome) were reported in both arms [10]. The second stage is ongoing and will assess efficacy based on progression-free survival in 730 men. A sub-study of the trial is comparing bone mineral density changes in the two trial arms, recruitment for which is now complete. Results from this sub-study, expected to be available in 2014, should further clarify the bone-protective role of oestrogen in this setting.

Based on such research, parenteral oestrogen may emerge as an effective single therapy for both treating prostate cancer and avoiding some of the adverse events associated with LHRHa administration, and may be particularly relevant for men with pre-existing risk of SKEs.