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Future directions in the treatment and prevention of bone metastases
1Cancer Research Centre, YCR Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield S10 2SJ, UK.
Abstract:
Preclinical studies are providing a growing body of evidence that bisphosphonates, particularly nitrogen-containing bisphosphonates, have antitumor activity. Bisphosphonates induce tumor cell apoptosis and reduce skeletal tumor burden in tumor xenograft models. Clinical studies with daily oral clodronate suggest that bisphosphonates can prevent bone metastases when used in the adjuvant setting, but the effect on overall survival is less certain. The more potent nitrogen-containing bisphosphonates, i.e., pamidronate and zoledronic acid, have demonstrated antitumor activity at approximately 10- to 100-fold lower concentrations than clodronate in vitro. A number of important unanswered questions must be addressed regarding the optimal use of bisphosphonates for prevention of bone metastases. For example, when should treatment begin, how long must treatment be continued, and what are the optimal dose and schedule to achieve clinically meaningful antitumor effects? Adjuvant studies of zoledronic acid in patients with breast and prostate cancer are under development, and the results are eagerly anticipated.
Insights
Bisphosphonates show antitumor effects, potentially preventing bone metastases. Further research is needed to determine optimal use for cancer patients, especially with nitrogen-containing bisphosphonates like zoledronic acid.
Area of Science:
- Oncology
- Pharmacology
Background:
- Bisphosphonates, especially nitrogen-containing ones, exhibit antitumor properties.
- Preclinical models show bisphosphonates induce apoptosis and reduce skeletal tumor burden.
- Clinical data suggests bisphosphonates may prevent bone metastases in an adjuvant setting.
Purpose of the Study:
- To review the evidence for bisphosphonates' antitumor activity.
- To identify key unanswered questions regarding the optimal use of bisphosphonates for preventing bone metastases.
- To highlight ongoing clinical trials investigating nitrogen-containing bisphosphonates.
Main Methods:
- Review of preclinical and clinical studies on bisphosphonates.
- In vitro assessment of antitumor activity of different bisphosphonates.
- Identification of knowledge gaps in bisphosphonate therapy for bone metastases.
Main Results:
- Bisphosphonates, particularly nitrogen-containing agents, demonstrate significant antitumor effects in preclinical models.
- Nitrogen-containing bisphosphonates are more potent than clodronate in vitro.
- Clinical evidence for preventing bone metastases exists, but impact on overall survival requires further investigation.
Conclusions:
- Bisphosphonates hold promise for preventing bone metastases and exhibiting antitumor activity.
- Optimal dosing, scheduling, and treatment duration for bisphosphonates remain critical research questions.
- Ongoing adjuvant studies, particularly with zoledronic acid, are crucial for advancing clinical application.