Treatment-Induced Bone Loss and Fractures in Cancer Patients Undergoing Hormone Ablation Therapy: Efficacy and Safety of Denosumab

Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture.

Pharmacotherapy Options in Cancer Treatment-induced Bone Loss: Focus on Bisphosphonates

Bone loss and its associated risk of fracture is a serious long-term health issue for breast cancer and prostate cancer survivors. Hormone ablation therapy, in particular aromatase inhibitors (AIs) for breast cancer and androgen deprivation therapy (ADT) for prostate cancer, causes marked reduction in circulating estrogen or testosterone levels, resulting in increased bone resorption, decreased bone mineral density (BMD), and an increased risk of fragility fracture. In several clinical trials with small sample sizes and short follow-up periods, oral and intravenous bisphosphonates have been shown to improve BMD, but not actual fracture rates, in cancer patients on hormone ablation therapy. A number of professional organizations and expert panels recommend the use of bisphosphonates for selected patients at risk. Although bisphosphonates are generally well tolerated, physicians should be aware of safety concerns, including the risk of osteonecrosis of the jaw. With the growing number of older breast and prostate cancer survivors, additional research is needed to characterize patients who would benefit from pharmacotherapy and optimize strategies to prevent cancer treatment-induced bone loss.

Effect of castration on endothelin receptors

Endothelin (ET) plays a pivotal role in the pathogenesis of cell growth disorders such as cancer. Atrasentan (ABT-627), a selective antagonist for the ET receptor A (ETA), has shown benefit in controlling disease progression in men with hormone refractory prostate cancer who have undergone aggressive hormone ablation therapy. It is not known how hormone ablation affects ET-binding sites, although ET-1 and ETA expression are found to be elevated in prostate cancer patients. In this study, we examined the effect of castration on ET receptor binding in male beagle dogs. Three dogs were surgically castrated and another three sham-operated. The animals were sacrificed 1 week after operation and membranes were prepared from the prostate, heart, brain, kidney, liver and lung for ET-1, ET-3 and angiotensin II (A-II, as a control) binding studies. No significant difference in A-II binding was observed between castrated and sham-operated animals. However, ET-1 and ET-3 binding to prostate and brain membranes were altered significantly. From saturation binding studies using ET-1 in the prostate, the Kd and Bmax values increased from 0.043nM and 0.094pmol/mg respectively in sham-operated dogs to 0.104nM and 0.311pmol/mg respectively in castrated animals. These results indicate that surgical castration in dogs produces a change in the ET receptor density in the prostate and brain, and may have implications for the effect of hormone ablation therapy on ET receptor expression in prostate cancer patients.