English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Tools annual

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Presents the access of premium content as premium feature

Premium Content

Global: Zendy Plus annual

Global: Zendy Free Plan

Bone metastases are frequent occurrences in prostate cancer. The discovery that prostate cancer is a hormone-dependent can- cer substantially altered strategies for treating this disease. Hor- mone therapy has since become the focus of much of the thera- peutic improvement in the management of advanced prostate cancer. The use of hormone therapy prior to the appearance of metastases has resulted in improved survival in randomized studies and has led to the widespread use of early, as well as adjuvant, hormone therapy. One of the drawbacks of long-term hormone therapy has been reported in recent studies on the effects of androgen-deprivation therapy on bone metabolism. We now realize that bone loss is evident over time and that men who receive such therapy have an increased risk of osteoporotic fractures (1). The class of compounds known as bisphosphonates have gen- erated interest as therapeutic agents for prostate cancer because of evidence that they reduce the risk of fracture among post- menopausal women with osteoporosis (2). However, only a few studies have examined the effects of various bisphosphonates on preventing bone loss among men undergoing androgen- deprivation therapy. For example, pamidronate, given intrave- nously every 3 months, was recently shown to prevent bone loss in men undergoing medical castration for prostate cancer (1). A subsequent study (3) reported that zoledronic acid, used intra- venously every 3 months to treat men undergoing medical cas- tration, was associated with an increase in bone mineral density over 1 year. No study to date has shown that either of these agents reduces the risk of fractures in a similar group of patients. Bisphosphonates have been shown to be effective in reducing bone complications in patients with osteolytic bone metastases due to multiple myeloma and breast cancer (4). It was long felt that prostate cancer, which produces osteoblastic metastases, would not be responsive to bisphosphonates because these agents primarily inhibit osteoclast function. However, results of a recent study (5) have revealed that bone resorption in meta- static prostate cancer is very high, reflecting substantial osteo- clastic activity. Therefore, there is biologic rationale for the use of bisphosphonates in prostate cancer to treat both the metasta- ses and the ongoing bone loss due to androgen deprivation. Unfortunately, early-generation bisphosphonates had not been shown to statistically significantly improve the outcomes of men with metastatic prostate cancer (6). In a recent report (7), the third-generation bisphosphonate zoledronic acid was shown to statistically significantly reduce the proportion of patients with hormone-refractory prostate cancer and bone metastases who experienced a skeletal-related event (SRE), including fractures, over 15 months. A statistically significant delay in the onset of the first SRE and a reduction in the overall rate of SREs over time were also observed. In this issue of the Journal, Dearnaley et al. (8) report on 311 men with hormone-sensitive metastatic prostate cancer who were randomly assigned to receive oral clodronate (a first- generation bisphosphonate) or placebo for 3 years. This was a very well-planned study with adequate follow-up to reach con- clusions about the efficacy of this bisphosphonate. The primary endpoint was symptomatic bone progression-free survival. Sec- ondary endpoints included overall survival and toxicity. The authors report a reduction in symptomatic bone progression-free survival in the clodronate group that did not reach statistical significance. Survival was better in the clodronate group than in the placebo group but did not reach statistical significance. The authors note, however, that statistically significantly more pa- tients in the clodronate group than in the placebo group experi- enced drug-related toxicity that required a reduction in drug dose. Results of a subgroup analysis appear to indicate that patients who began therapy when their cancer was at an earlier stage of metastasis had better outcomes than patients who began therapy when their cancer was at a later stage of metastasis. The inability to demonstrate a statistically significant benefit using clodronate in metatstatic prostate cancer may be due to several factors. First, the bioavailability of oral bisphosphonates

Bisphosphonates in Prostate Cancer: Where Are We and Where Should We Go?