Targeting Bone Metabolism in Patients with Advanced Prostate Cancer: Current Options and Controversies

Maintaining bone health remains a clinical challenge in patients with prostate cancer (PC) who are at risk of developing metastatic bone disease and increased bone loss due to hormone ablation therapy. In patients with cancer-treatment induced bone loss (CTIBL), antiresorptive agents have been shown to improve bone mineral density (BMD) and to reduce the risk of fractures. For patients with bone metastases, both zoledronic acid and denosumab delay skeletal related events (SREs) in the castration resistant stage of disease. Novel agents targeting the Wnt inhibitors dickkopf-1 and sclerostin are currently under investigation for the treatment of osteoporosis and malignant bone disease. New antineoplastic drugs such as abiraterone, enzalutamide, and Radium-223 are capable of further delaying SREs in patients with advanced PC. The benefit of antiresorptive treatment for patients with castration sensitive PC appears to be limited. Recent trials on the use of zoledronic acid for the prevention of bone metastases failed to be successful, whereas denosumab delayed the occurrence of bone metastases by a median of 4.1 months. Currently, the use of antiresorptive drugs to prevent bone metastases still remains a field of controversies and further trials are needed to identify patient subgroups that may profit from early therapy.

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Randomized Controlled Trial of Annual Zoledronic Acid to Prevent Gonadotropin-Releasing Hormone Agonist–Induced Bone Loss in Men With Prostate Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.07.3361 ◽

2007 ◽

Vol 25 (9) ◽

pp. 1038-1042 ◽

Cited By ~ 224

Author(s):

M. Dror Michaelson ◽

Donald S. Kaufman ◽

Hang Lee ◽

Francis J. McGovern ◽

Philip W. Kantoff ◽

...

Keyword(s):

Prostate Cancer ◽

Lumbar Spine ◽

Zoledronic Acid ◽

Bone Loss ◽

Gnrh Agonist ◽

Controlled Trial ◽

Gonadotropin Releasing Hormone ◽

Mineral Density ◽

Releasing Hormone ◽

Increase Fracture Risk

Purpose Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Annual zoledronic acid increases BMD in postmenopausal women, but its efficacy in hypogonadal men is not known. Patients and Methods In a 12-month study, 40 men with nonmetastatic prostate cancer who were receiving a GnRH agonist and had T scores more than −2.5 were randomly assigned to zoledronic acid (4 mg intravenously on day 1 only) or placebo. BMD of the posteroanterior lumbar spine and proximal femur were measured by dual-energy x-ray absorptiometry. Results Mean (± SE) BMD of the posteroanterior lumbar spine decreased by 3.1% ± 1.0% in men assigned to placebo and increased by 4.0% ± 1.0% in men assigned to zoledronic acid (P < .001). BMD of the total hip decreased by 1.9% ± 0.7% in men assigned to placebo and increased by 0.7% ± 0.5% in men assigned to zoledronic acid (P = .004). Similar between-group differences were observed for the femoral neck and trochanter. Serum N-telopeptide, a marker of osteoclast activity, decreased significantly after zoledronic acid treatment. Conclusion In men receiving a GnRH agonist, a single treatment with zoledronic acid significantly increased BMD and durably suppressed serum N-telopeptide levels for 12 months. Annual zoledronic acid may be a convenient and effective strategy to prevent bone loss in hypogonadal men.

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Effect of zoledronic acid (ZA) versus placebo on bone mineral density (BMD) in androgen-deprived prostate cancer patients with and without bone metastases (mets)

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.4760 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 4760-4760

Author(s):

C. W. Ryan ◽

D. Huo ◽

M. Hanson ◽

W. M. Stadler ◽

N. J. Vogelzang

Keyword(s):

Prostate Cancer ◽

Bone Mineral Density ◽

Zoledronic Acid ◽

Bone Metastases ◽

Cancer Patients ◽

Bone Mineral ◽

Mineral Density

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Annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: A randomized placebo-controlled trial

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4515 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4515-4515 ◽

Cited By ~ 3

Author(s):

M. D. Michaelson ◽

H. Lee ◽

D. S. Kaufman ◽

P. W. Kantoff ◽

J. Finkelstein ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Mineral Density ◽

Lumbar Spine ◽

Zoledronic Acid ◽

Bone Loss ◽

Bone Mineral ◽

Gnrh Agonist ◽

Gonadotropin Releasing Hormone ◽

Mineral Density ◽

Total Hip

4515 Background: Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Zoledronic acid (4 mg IV every 3 months) increases BMD in GnRH agonist treated men. Intermittent zoledronic acid (4 mg IV once annually) increases BMD in postmenopausal women with osteoporosis but the efficacy of the annual treatment schedule in hypogonadal men is unknown. Methods: In a 12-month open-label study, men with nonmetastatic prostate cancer (n = 44) who were receiving a GnRH agonist were assigned randomly to zoledronic acid (4 mg IV × 1) or placebo. BMD of the posteroanterior lumbar spine and total hip were measured by dual energy x-ray absorptiometry at baseline and month 12. Serum N-telopeptide, a marker of osteoclast activity, was measured every 3 months. Results: Mean (± SE) BMD of the posteroanterior lumbar spine increased by 4.0 ± 0.9 in men treated with zoledronic acid and decreased by 3.1 ± 0.9 percent in men who received placebo (P < 0.001 for between-group comparison). BMD of the total hip decreased by 0.7 ± 0.6 percent in men treated with zoledronic acid and decreased by 1.9 ± 0.7 percent in men who received placebo (P = 0.005). Compared to placebo, zoledronic acid significantly decreased serum N-telopeptide throughout the 12-month study (P < 0.05). Conclusions: In men receiving a GnRH agonist for prostate cancer, a single treatment of zoledronic acid significantly increased bone mineral density of the total hip and spine at 12 months. Annual zoledronic acid may provide a convenient and effective strategy to prevent bone loss in hypogonadal men. This study was supported in part by Novartis Oncology and by the Prostate Cancer Foundation. [Table: see text]

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The role of bisphosphonates in breast and prostate cancers.

Endocrine Related Cancer ◽

10.1677/erc.0.0110207 ◽

2004 ◽

Vol 11 (2) ◽

pp. 207-224 ◽

Cited By ~ 97

Author(s):

Janet E Brown ◽

Helen Neville-Webbe ◽

Robert E Coleman

Keyword(s):

Breast Cancer ◽

Zoledronic Acid ◽

Bone Loss ◽

Bone Mineral ◽

Bone Disease ◽

Bone Pain ◽

Metastatic Bone Disease ◽

Mineral Density ◽

Intravenous Pamidronate ◽

Oral Clodronate

Bisphosphonate drugs are a group of pyrophosphate analogues which bind avidly to hydroxyapatite bone mineral surfaces and their major action is to inhibit osteoclast activity and thus bone resorption. In oncology, their role in metastatic bone disease is well established, but there is increasing interest in their potential role in preventing and treating cancer-induced bone loss and their possible anti-tumour effects. Metastatic bone disease is associated with a variety of skeletal complications, including pathologic fractures, bone pain, impaired mobility, spinal cord compression and hypercalcaemia. Intravenous bisphosphonates, particularly zoledronic acid, in conjunction with rehydration, are now established as the treatment of choice for hypercalcaemia. For treatment of bone pain, it has also been shown that bisphosphonates can be an effective supplementary approach to radiotherapy. In breast cancer and myeloma, bisphosphonates have now become part of standard therapy to treat and prevent skeletal-related events (SRE) and, until recently, treatment was largely with intravenous pamidronate or oral clodronate. However, large, randomised, multicentre trials using intravenous administration of the highly potent bisphosphonate zoledronic acid every 3-4 weeks have recently demonstrated a reduction of 20% in the risk of developing an SRE compared with pamidronate for patients with breast cancer. Moreover, these trials have demonstrated, for the first time, that a bisphosphonate significantly reduces the occurrence of skeletal events in hormone-refractory prostate cancer and in non-small cell lung cancer and a range of other solid tumours. Investigations into the potential of the relatively low potency bisphosphonate, clodronate, for the prevention of bone metastases in breast cancer have produced conflicting data. Further large, randomised studies with clodronate and zoledronic acid are planned and until the results are available it is not possible to identify a definite adjuvant role for bisphosphonates. Evidence is accumulating in vitro that bisphosphonates are also able to directly affect tumour cells, in addition to their effects on osteoclasts, with zoledronic acid being particularly potent. Over recent decades there has been a significant improvement in cure rates and survival times in certain cancers and the use of chemotherapy and hormone therapy has expanded greatly, leading to increasing numbers of long-term survivors who have received these treatments. Management of treatment-induced bone loss is therefore assuming a greater importance and bisphosphonates represent an attractive treatment option in such patients. Several placebo-controlled trials using oral clodronate, oral risedronate, intravenous pamidronate and intravenous zoledronic acid have all now demonstrated benefits in reducing the loss in bone mineral density.

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The effects of intermittent androgen deprivation therapy (ADT) and zoledronic acid administration on bone density in patients with prostate cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.15593 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 15593-15593 ◽

Cited By ~ 1

Author(s):

L. Katznelson ◽

K. Kent ◽

S. Srinivas

Keyword(s):

Prostate Cancer ◽

Lumbar Spine ◽

Zoledronic Acid ◽

Bone Loss ◽

Femoral Neck ◽

Previous Treatment ◽

Osteonecrosis Of The Jaw ◽

Recurrent Prostate Cancer ◽

Mineral Density ◽

Acid Administration

15593 Background: Intermittent ADT is commonly used in men with recurrent prostate cancer. Bone loss associated with ADT is well described. Bisphosphonate use in men undergoing ADT results in improvement in bone mineral density (BMD), although the utility and duration of bisphosphonate use in men undergoing intermittent ADT are unclear. Objective:To evaluate the effect of zoledronic acid administration every 3 months on BMD in men with prostate cancer undergoing intermittent ADT, and whether BMD is maintained upon discontinuation of both ADT and zoledronic acid. Methods: Patients with recurrent prostate cancer starting ADT were eligible to participate. Subjects received ADT for 9 months in addition to 3 doses of zoledronic acid every 3 months. At 9 months, patients who achieved an undetectable serum PSA were taken off ADT and then randomized either to continuing zoledronic acid every 3 months for an additional 3 doses vs. observation. BMD, assessed by DEXA scan, was determined at baseline, 9 months, and between 18 -24 months at hip, trochanter, femoral neck and lumbar spine sites. Results: Twenty two patients were treated with ADT and zoledronic acid between 2003–2006. Seven of these subjects had bone metastases and had previous treatment with ADT.There was one infusion related reaction, and one patient developed osteonecrosis of the jaw and was removed from the study. At baseline, 3 patients had osteoporosis at the lumbar spine. All patients who received zoledronic acid for 9 months had an improvement in BMD at all 3 sites. In the 7 subjects who had previously received ADT, BMD of the femoral neck increased significantly by approximately 1.9%. Among the 6 patients randomized to continuing zoledronic acid after discontinuing ADT at 9 months, all had a further, significant increase in BMD. Those randomized to observation were unable to maintain their BMD and had continued bone loss despite stopping ADT. Conclusions: This small study demonstrated an increase/maintenance of BMD in men receiving intermittent ADT and zoledronic acid. Only those men who continued zoledronic acid for up to a total of 9 mos after discontinuing ADT maintained BMD No significant financial relationships to disclose.

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