Bone metastases are highly prevalent in patients with prostate cancer, and they commonly present a therapeutic challenge. The natural history of prostatic bone metastases is characterized by skeletal morbidity, often producing distressing symptoms for individual patients and reducing patient autonomy and mobility. These bone metastases are usually radiologically osteoblastic, but there is also a strong osteolytic component as evidenced by marked increases in bone resorption markers. Malignant bone lesions can reduce the structural integrity of the skeleton, resulting in skeletal complications such as pathologic fracture, spinal cord compression, and severe bone pain, which adversely affect quality of life.
Preclinical and clinical studies have provided insight into the pathophysiology of malignant bone disease from prostate cancer and suggest that bone-directed therapies, including radionuclides, endothelin-1 antagonists, and bisphosphonates, may provide both palliative and therapeutic benefits. Clinical investigations with these agents are underway in patients with prostate cancer to gain insight into the pathophysiology of bone metastases and to evaluate the role of bone-specific therapies in treating and preventing bone metastases.
Keywords: Bone metastasis, Osteoclast, Osteoblast, Prostate cancer, Skeletal complications.
Prostate cancer is the most common genitourinary tract malignancy; its prevalence is especially high in North America and Western Europe
Prostate cancer metastasizes to bone in approximately 65% to 75% of men with advanced disease
2. Prostate cancer metastasis to bone
Prostate cancer metastasizes to bone more frequently than does any other solid tumor
Metastasis to bone via the circulatory or lymphatic system is a multistep process (
2.1. Early steps in metastases to bone
Metastasizing cells arrest in the bone marrow endothelium, where they are immobilized in capillary beds. Tumor cell binding is a rapid and highly selective process, with tumor cells binding to specific endothelial cells at preferred metastatic sites and actively migrating through gap junctions , , and . This process of extravasation is complete within 24
It has also been hypothesized that growth factors released during osteolysis can stimulate the growth not only of osteoblasts but of tumor cells that metastasize to bone. Indeed, preclinical evidence suggests that bone resorption (osteoclast-mediated osteolysis) may be a crucial element in the development of bone metastases , , , and . However, this evidence, although compelling, has not been validated in human bone metastases.
2.2. Formation of bone lesions
Once established within the bone microenvironment, prostate cancer cells and the cells that maintain skeletal homeostasis participate in a complex interplay that results in perturbations of bone metabolism and increases in tumor growth. During osteolysis, growth factors contained in the bone matrix, predominantly transforming growth factor-beta (TGF-β) and insulinlike growth factor 2 (IGF2), are released, causing paracrine stimulation of osteoblasts to repair the bone at the site where osteolysis occurred. This coupled activity preserves the structural integrity of the skeleton and contributes to serum ion homeostasis  and .
The pro-osteogenic effects of prostate cancer tumors are mediated through complex interactions between tumor and bone. Metastatic prostate cancer cells secrete TGF-β and endothelin-1 (ET-1), which exert localized effects on bone metabolism (
3. Clinical consequences of bone metastases
In patients with prostate cancer, metastasis to bone is often accompanied by the onset of severe bone pain and other complications, including pathologic fracture and spinal cord compression, similar to patients with predominantly osteolytic bone lesions
Although osteoblastic lesions are associated with pathologic new bone formation, this does not correlate with increases in bone strength. On the contrary, the new osseous tissue is often abnormally mineralized or inappropriately placed , , and . Furthermore, osteoblastic bone metastases can trigger localized increases in osteolysis to balance the excess activity of osteoblasts , , , , , and . Excess osteogenesis can also cause systemic increases in osteolysis, resulting in generalized osteolysis at distant sites. The overall result is uncoupling of the osteogenesis and osteolysis processes. In most cases, disease progression in patients with bone metastases from prostate cancer is associated with mild hyperparathyroidism
The effects of bone metastases secondary to hormone-refractory prostate cancer are illustrated by the placebo-control arm of a recent randomized clinical trial of zoledronic acid  and . Although all patients in this trial were receiving standard therapy for their primary cancer, 49% of patients experienced at least 1 skeletal complication over 2 years of follow-up, and these events occurred at an average rate of 1.5 skeletal complications per patient per year (patients who experienced skeletal complications had a mean incidence of approximately 3 events per year)
A recent retrospective review of clinical records of men with prostate cancer treated during a 4-year period (N
Skeletal complications have been shown to significantly reduce health-related quality of life in patients with prostate cancer
Skeletal complications from prostate cancer may have severe long-term effects. Pathologic fractures can have especially grim implications because the majority require radiotherapy and/or orthopedic surgery. Additionally, extensive rehabilitation is required to restore function when weight-bearing bones are involved
There is a consistent correlation of skeletal disease burden with bone metabolism and survival
4. Effects of ADT on the skeleton
Chemotherapy and hormone therapy are associated with bone loss in cancer patients
Several studies have investigated the effects of ADT on bone loss in men with prostate cancer. Eriksson et al.
Antiandrogen therapy, which blocks the androgens locally in the prostate, is indicated in the United States for use in combination with an LHRH agonist. Although data are sparse on the skeletal effects of combination therapy, antiandrogen (bicalutamide) monotherapy has demonstrated an increased BMD from baseline by 2.5% in the lumbar spine at 12 months in men with prostate cancer and no metastases
5. Monitoring of bone mineral density in patients receiving ADT
It has been suggested by an expert panel that men undergoing ADT should have routine assessments of BMD
In addition to the measurement of BMD to evaluate the effects of ADT on the skeleton, other biologic exams such as serum 25-hydroxyvitamin D levels should be considered
Biochemical markers of bone metabolism provide insight into the ongoing levels of osteolysis and osteogenesis in patients with malignant bone disease
6. Role of bisphosphonates in prostate cancer
Zoledronic acid, clodronate, pamidronate, and ibandronate have all been investigated in patients with bone metastases from prostate cancer , , , , and , and all have shown some benefit in terms of pain palliation. However, only zoledronic acid has demonstrated long-term, objective benefits compared with placebo. In a phase III randomized, placebo-controlled trial, zoledronic acid significantly reduced the percentage of patients with skeletal complications and reduced bone pain
Recent studies have demonstrated that IV bisphosphonate therapy can prevent CTIBL in men receiving ADT for nonmetastatic prostate cancer. Compared with placebo, pamidronate (60
Current treatment algorithms for patients with prostate cancer support the use of zoledronic acid to reduce the incidence of skeletal complications from bone metastases and the use of bisphosphonates to prevent bone loss during ADT  and . By reducing osteolysis in patients with early-stage disease, bisphosphonates may better protect patients from skeletal complications later in the disease course and may prevent bone metastasis. It should be noted, however, that not all skeletal complications in this patient population arise specifically from bone metastases.
7. Novel treatments for prostate cancer
Although bisphosphonates have demonstrated clinically significant reductions in the incidence of skeletal complications from bone metastases and palliation of bone pain in patients with metastatic disease, no available therapy has been shown to improve survival or delay disease progression in patients with advanced prostate cancer. Clearly, novel agents are needed to address these issues. Two therapeutic regimens currently being investigated for the treatment of metastatic prostate cancer are the ETs and radionuclides.
7.1. Endothelin receptor antagonists
Endothelin-1 is a small peptide that interacts with a G-protein–coupled receptor, ETA, to mediate the processes of tissue differentiation, repair, and growth through a complex intracellular signaling pathway. Recently, ET-1 has been implicated in prostate tumor cell progression through signaling of mitogenesis, inhibition of apoptosis, and modulation of angiogenesis and osteogenesis. Endothelin-1 is produced in the prostate gland, and ETA receptor expression is up-regulated in prostate cancer
Recently, the ETA antagonist atrasentan (ABT-627; Abbott Laboratories, Abbott Park, Ill, USA) was shown to dose-dependently suppress markers of bone formation in patients with bone metastases from prostate cancer
Two large, multinational, double-blind, randomized, placebo-controlled trials in 2 different prostate cancer populations are currently ongoing. A third study, M00-211, was stopped in February 2003 because it was decided that the study did not meet the primary endpoint of time-to-disease progression
7.2. Radiotherapy and radionuclides
Metastatic prostate cancer is associated with severe, debilitating bone pain that is often refractory to supportive care with analgesics. Current therapies to manage pain include external beam radiation therapy and/or radiopharmaceuticals. Radiation therapy has been shown to reduce tumor size, decrease osteolysis, and decrease cancer burden
External beam radiation is typically delivered locally for bone pain. However, it can be delivered systemically if symptoms are widespread. Adverse events including nausea, headache, weight loss, and hair loss are often reported. Late, chronic side effects such as fatigue may also limit the dose of radiation that can be given
Use of radionucleotide therapy can directly target bone. Metal-chelated radiopharmaceuticals such as 153Sm-EDTMP and 117mSn-DTPA adsorb to the trabecular surface of the bone, whereas 32P and 89Sr are more widely distributed in the bone
Maintaining bone health in patients with prostate cancer is an important goal. Reductions in BMD occur in patients receiving ADT; therefore, they have an increased risk for skeletal fractures. It is recommended that men undergoing ADT have routine BMD assessments. Current treatment algorithms support the use of bisphosphonates to prevent bone loss during ADT.
Patients with prostate cancer are at high risk for developing bone metastases during disease progression
Zoledronic acid has demonstrated long-term benefits compared with placebo in patients with prostate cancer and bone metastases. Zoledronic acid therapy has significantly reduced the incidence of skeletal complications and bone pain in this patient population. Additionally, recent data suggest that zoledronic acid effectively inhibits CTIBL. The potential benefits of zoledronic acid throughout the natural history of prostate cancer progression continue to be investigated.
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a Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Montréal, Québec, Canada
b Christie and Hope Hospitals, Manchester, UK
c Hopital Edouard Heriot, Lyon, France
© 2005 Elsevier B.V., All rights reserved.