Bone Metastases In Men Research Articles

Osteoclast-targeted therapy for prostate cancer.

Skeletal complications are a major cause of morbidity in men with metastatic prostate cancer. Bone metastases cause pain, fractures, spinal-cord compression, and ineffective hematopoiesis. Men without bone metastases are also at risk for skeletal complications. Androgen deprivation therapy (ADT), the mainstay of treatment for metastatic prostate cancer and a routine part of the management for many men with nonmetastatic prostate cancer, decreases bone mineral density, and increases fracture risk. Pathological osteoclast activation plays a central role in both disease and treatment-related skeletal morbidity. Bisphosphonates, potent inhibitors of osteoclast activity, are now an important part of the management for many men with prostate cancer. Zoledronic acid, a potent intravenous bisphosphonate, decreases the risk of skeletal complications in men with hormone-refractory prostate cancer and bone metastases. Zoledronic acid and pamidronate preserve bone mineral density in men receiving ADT for nonmetastatic prostate cancer. Ongoing clinical trials will evaluate the role of osteoclast-targeted therapy in other settings including prevention of treatment-related fractures, prevention of bone metastases in men with high-risk nonmetastatic prostate cancer, and prevention of skeletal complications in men with hormone-sensitive metastatic disease.

Future Directions for Zoledronic Acid and New Agents for the Treatment of Bone Metastases

Objective: Zoledronic acid has demonstrated clinical benefit in both early and advanced-stage prostate cancer for the prevention of bone loss and treatment of bone metastases. Herein, the future role of zoledronic acid in the treatment of prostate cancer and novel agents with potential clinical benefit for the treatment of bone metastases will be discussed. Methods: Published studies were identified through MEDLINE searches, review of bibliographies of relevant articles, and review of abstracts from scientific meetings. Results: Data from preclinical studies have demonstrated that zoledronic acid has antitumor potential. Zoledronic acid inhibits proliferation and induces apoptosis in several prostate cancer cell lines and inhibits bone metastases in animal models of prostate cancer. Therefore, clinical trials are under way to assess the efficacy of zoledronic acid in the prevention of bone metastases in patients with prostate cancer or renal cell carcinoma. Currently, new strategies for the treatment and prevention of bone metastases are being investigated. Combinations of zoledronic acid plus other agents, including taxanes and cyclooxygenase-2 (COX-2) inhibitors, have demonstrated additive or synergistic antitumor activity. Other agents are under development that may improve clinical outcomes in patients with bone metastases. These agents include inhibitors of osteoclast-mediated bone resorption, such as cathepsin K inhibitors and osteoprotegerin analogues, and inhibitors of osteoblast activity. Conclusion: The role of zoledronic acid in the treatment and prevention of bone metastases in men with prostate cancer continues to evolve, and new agents are being investigated.

Bisphosphonates to Prevent Skeletal Complications in Men With Metastatic Prostate Cancer

The literature on clinical trials of bisphosphonates in men with metastatic prostate cancer is reviewed to familiarize the reader with biology of bone metastases and rationale for use of bisphosphonates. A MEDLINE review of the literature on prostate cancer and bisphosphonates was performed. In uncontrolled clinical trials bisphosphonates improved pain and analgesic scores in men with symptomatic bone metastases. In a randomized controlled trial of men with bone metastases and progressive disease after first line hormonal therapy zoledronic acid decreased the skeletal related events, a composite end point defined as fracture, surgery or radiation therapy to bone, or change in antineoplastic therapy for bone pain. Randomized controlled trials with other bisphosphonates reported no significant benefit in men with bone metastases. Problems with the study populations, drug bioavailability and potency, statistical power and end point definition may have contributed to the negative results of these other studies. Zoledronic acid decreases the risk of skeletal related events in men with bone metastases and disease progression after first line hormonal therapy. Additional clinical research is needed to evaluate the optimal timing, schedule and duration of bisphosphonate treatment in men with metastatic prostate cancer. Additional research is also necessary to determine whether bisphosphonates can prevent bone metastases in men with high risk nonmetastatic prostate cancer.

Are serial bone scans useful for the follow-up of clinically localized, low to intermediate grade prostate cancer managed with watchful observation alone?

To assess the predictive value of serial bone scans as a surveillance tool for bone metastasis in men with clinically localized prostate cancer and managed with watchful observation. A prospective single-arm study was conducted to assess the feasibility of a watchful observation protocol with selective delayed intervention for patients with clinically localized prostate cancer, i.e. T1b-T2bN0M0, a Gleason score of <or= 7 and a prostate-specific antigen (PSA) level of <or= 15 ng/mL. Patients were managed expectantly as long as they did not meet the empirically predefined criteria of clinical, histological or PSA progression. Bone scintigraphy was repeated every year for the first 2 years, then every 2 years thereafter if the patient remained on watchful observation. When the follow-up PSA level was > 15 ng/mL the patient underwent bone scintigraphy every year. In all, 244 eligible patients were enrolled into the study. With a median follow-up of 30 months, 449 bone scans were taken (150 at baseline and 299 in follow-up evaluations); all 299 follow-up scans were negative for bone metastasis. Hence, the true rate of positive follow-up bone scans was estimated to be 0-1.0% (95% confidence). In all, 171 patients had at least one follow-up bone scan; of these, the number (%) of patients who had 1, 2, 3, 4 and >or= 5 follow-up scans was 89 (52), 53 (31), 17 (10), eight (4.7) and four (2.3), respectively. The PSA levels (ng/mL) corresponding to all follow-up bone scans were: 214 scans at PSA < 10, 61 at 10-14.9, 18 at 15-19.9 and six at >or= 20 (range 20.2-24.9). The probability of a negative bone scan was estimated to be 88-100% (95% confidence interval) when a PSA threshold of 15 ng/mL was used. The probability of positive findings in serial bone scans in untreated, localized, low to intermediate grade prostate cancer was low when the follow-up PSA level remained < 15 ng/mL. Avoiding bone scans in this group of patients would translate into a significant cost saving and reduction in their psychological and physical burden. As for those with a follow-up PSA of> 15 ng/mL, the role of serial bone scintigraphy remains undefined, as a longer follow-up and a larger sample are needed.