Diagnosis of bone metastases in urological malignancies—an update

Introduction

Bone is a common site for spread of cancer. In regard to urological malignancies, prostate cancer has the highest incidence of bony metastatic spread being reported as up to 84% [ , ]. Other malignancies such as kidney and bladder also metastasize to bone, however are less common ( Table 56.1 ). Bone metastases complications can be debilitating for patients, resulting in skeletal-related events such as severe pain, pathological fractures, spinal cord compression, hypercalcemia, and nerve compression syndromes.

The presence of bony metastases can also have prognostic value. For prostate cancer, around half of patients with bony metastases detected will succumb within 30 months of detection [ , ]. Figures show that in excess of 350,000 people with a variety of malignancies in the United States die with bone metastases [ ].

Given the high blood flow in areas of red marrow, bone is a preferred site for the spread of cancer. Adhesive molecules produced by tumor cells bind to marrow stromal cells and bone matrix. Furthermore, there is a large reservoir for immobilized growth factors [ ]. Despite this knowledge, it is difficult to predict the tendency of tumors to spread to bone because patients who succumb to cancer early from an aggressively growing malignancy do not have enough time for metastases to develop.

Bone metastases can be osteoblastic (bone forming) or osteolytic (bone destructive) ( Table 56.1 ). The majority of cancers are a combination of the two. At the extreme end of the spectrum, multiple myeloma is purely lytic, while prostate cancer is predominately osteoblastic [ ].

Prevention of complications caused by bony metastases through early detection can reduce patient morbidity and cost to the community. As part of the assessment and surveillance of malignancies, clinical assessment, bone markers, radiological imaging, and tissue biopsies are vital tools used in the diagnosis of bony spread. It will allow the implementation of treatment strategies such as surgical fixation, radiotherapy, or bisphosphonate therapy to improve quality of life [ ].

A proactive role has been taken in detecting and then treating bone metastases with benefit to the patient as well as potentially reducing costs. A seminal report by Saad and colleagues looked at men with hormone-resistant prostate cancer with bone metastases [ ]. These men were divided into two groups: those who were symptomatic and those without symptoms of bony lesions. Participants were given the bisphosphonate, zoledronic acid, and compared to a control group. The results showed that there was a 39% relative reduction in bone metastatic complications in the asymptomatic group and 19% relative reduction in the symptomatic group when compared to untreated patients. This indicates that bisphosphonate therapy has a valuable role in the early treatment of metastatic disease and paved the way for the bone health focus now taken in prostate cancer. Building upon this paradigm are studies that now consider men with hormone-naïve disease whereby those with oligometastatic disease potentially have benefit from radiation treatment to an isolated site in the hope of delaying disease progression [ ].

A clinical suspicion of possible bony spread is ascertained with history and examination. This will guide and rationalize the array of investigations available to gather further evidence of metastases.

History and examination

A physician should be able to determine a level of suspicion of metastatic spread of a malignancy by the clinical assessment of a patient. Using the fundamentals of history and examination, as well as disease tempo, investigations can be rationalized to answer the clinical question.

Serum and bone markers for bone metastases

Bone undergoes regular remodeling. It is a balance between bone resorption, which is controlled by osteoclasts and bone formation governed by osteoblasts. These two processes are tightly coupled together to maintain bone mass. However, metabolic bone diseases including bone metastases alter this balance.

When cancer cells enter into the bone marrow, they disrupt normal bone cell turnover by releasing local cytokines and growth factors. This eventually leads to the net result of osteolysis or osteosclerosis. Some malignancies secrete factors that stimulate osteoclasts, such as parathyroid hormone–related protein, tumor necrosis factor α or β, and other cytokines such as interleukins 1 and 6. For sclerotic lesions, cancer cells commonly secrete factors such as epidermal growth factor, transforming growth factor α and β, and insulin-like growth factors that stimulate osteoblast activity [ , ].

Different malignancies secrete mixed number factors, resulting in net bone resorption or formation. This can be evaluated by gauging prominent enzymatic activity of bone-forming or bone-resorbing cells, or by measuring bone matrix breakdown products released into circulation during bone formation or resorption. These bone turnover markers are grouped into bone formation or bone resorption.