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Keywords:

  • bone metastasis;
  • detection;
  • prediction;
  • treatment
Abbreviations
BMP

bone morphogenetic protein

NICE

National Institute of Clinical Excellence

SPECT

single-photon emission CT

PET

positron emission tomography.

INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES

Prostate cancer has emerged as the commonest cancer in Europe and the USA, where up to 265 000 men are being diagnosed annually [1]. It is also the second leading cause of cancer-related deaths in the USA, with 31 500 cases in 2001. The advent of PSA as a screening tool and increased public awareness has produced a significant downward migration of tumour stage in prostate cancer, whereby patients are now presenting earlier with curable organ-confined disease. However, up to 22% of newly diagnosed patients are still presenting with advanced or metastatic disease [2].

Bone is the commonest site of spread and accounts for up to 80% of all prostate cancer metastases; half of men with metastatic disease die within 30 months and 85–100% of those who die from prostate cancer have bone metastases [3,4]. Although metastatic bone disease may initially be asymptomatic, ultimately most patients have symptoms ranging from bone pain to pathological fractures and spinal cord compression. Tumour volume and site in the bone have proved to be important determinants of symptom severity and prognosis for patients with metastatic prostate cancer [5].

The effective detection of early bone metastases is important in patients being considered for radical therapy, and may be useful in more advanced disease, as there is some evidence that early treatment may reduce complications and improve survival. To improve the methods of early detection of bone metastases it is important to understand that the invasion and progression of bone metastases is related to alterations in bone biology.

METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES

Over a century ago, Paget's ‘seed and soil’ theory described the predisposition for certain cancers to favourable sites, such as the skeleton, likening it to plant seeds flourishing in congenial soil [6]. More recently, this metastatic process has been suggested to be a specific pathway determined by properties of both tumour cells and the destined metastatic site [7].

Prostate tumour cells most commonly metastasize via the haematogenous route to well-vascularized areas of the skeleton, particularly the red bone marrow of the axial skeleton. These cells access Batson's plexus, which is a low-pressure, high-volume communication between the pelvic and vertebral veins [2]. The vertebral column is therefore the first site for prostate tumour cells to invade.

Normal bone biology involves interactions between several cell types and their mediators to control bone remodelling in the dynamic skeleton. Bone remodelling is a balanced process of bone synthesis and resorption (osteoblastic and osteoclastic activity). Osteoblasts, derived from mesenchymal stem cells, form bone over ≈ 3 months by producing collagen and bone proteins, and causing the mineralization of bone matrix. Osteoclasts, cells originally from monocyte/macrophage precursors, break down bone over a 3-week period by releasing acid, collagenases and proteases to dissolve the organic and mineral content of bone [8].

Bone biology is altered once tumour invades the skeleton. Malignant bone disease may be focal or generalized, osteolytic or osteosclerotic and cause three distinct changes to bone remodelling [8]. First, there is increased bone turnover, where both osteoblastic and osteoclastic activities become more vigorous. This increased activity is thought to be caused by bone-derived factors such as bone morphogenetic proteins (BMPs) and parathyroid hormone-related peptide, respectively. Second, there may be focal imbalances between osteoblastic and osteoclastic activity that would lead to either osteosclerotic or osteolytic lesions. Third, uncoupling occurs, where there may be left-over cavities after bone breakdown without subsequent bone formation.

A ‘vicious cycle’ has been postulated to occur during the metastatic process in bone from prostate cancer (Fig. 1). It has been proposed that when prostate carcinoma cells first invade bone matrix, signalling between these cells and osteoblastic cells then causes the release of BMPs from bone matrix to trigger new bone formation. New bone formation causes a positive feedback that allows further release of these growth factors, not only from the bone matrix but also from the carcinoma cells within the matrix. This cascade compounds further bone formation and proliferation which leads to osteosclerosis. As more metastatic cells invade bone, this cascade leads to increased intra-osseous pressure and peri-osteal elevation in bone, which subsequently causes bone pain and fractures [9].

image

Figure 1. The ‘vicious cycle’ in prostatic bone metastasis.

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TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES

Prostatic bone metastases can be treated with external beam radiotherapy, radioisotope therapy, hormone deprivation and bisphosphonate treatment. External beam radiotherapy has been used to relieve bone pain at either solitary or multiple sites by local-field or wide-field radiation. For local-field radiotherapy a higher dose with fractionated treatments produces a better response, with more pain relief than the low-dose, single-fraction regimens [10]. For multiple metastatic sites wide-field radiation therapy provides a suitable systemic approach. If problems related to radiation exposure of sensitive structures, e.g. lungs, gut and kidney, arise then the radiation fields may be shaped for the half-body or hemibody. Radioisotope therapy is another method of providing systemic radiotherapy where radiopharmaceuticals like 32P and 89Sr have been administered. Although this method of delivering radiation directly to the site of metastatic disease seems ideal, previous studies have shown no benefit in palliation when compared to either local or hemibody radiation therapy [11,12].

Early hormone deprivation has been shown to delay disease progression and may even improve survival [13]. However, ‘castrating’ hormonal treatment may itself contribute to osteoporosis, leading to bone pain and fractures. This is an increasingly important consideration as more men are starting hormone-deprivation therapy much earlier in the disease process, e.g. those with biochemical recurrence after radical prostatectomy. Bisphosphonates are stable analogues of pyrophosphate that are thought to alter the ‘vicious cycle’, by affecting the bone microenvironment [14]. The new generation of bisphosphonates are thought to have cytotoxic effects on osteoclasts to reduce bone resorption, and direct cytotoxic and apoptotic actions on tumour cells. In vitro studies have shown that bisphosphonates can halt the progression and even cause regression of tumours [15].

ESTABLISHED METHODS FOR PREDICTING BONE METASTASES

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES

PSA has revolutionized the diagnosis of prostate cancer and is widely used to monitor disease progression, response to therapy and disease recurrence. PSA can also be used to some extent to predict disease severity and prognosis. PSA progressively increases with increasing clinical stage of prostate cancer, and with increasing pathological stage and tumour volume. In patients with prostatic bone metastases, a rising PSA precedes changes on their bone scan by several months.

In 1993, Oesterling et al.[16] evaluated patients from the Mayo Clinic over 2 years and concluded that it is not necessary to use bone scans in patients newly diagnosed with prostate cancer, with a PSA level of < 10 ng/mL and no skeletal symptoms, as the possibility of an abnormal bone scan in these patients was 0.5%. They also noted that there would be significant cost savings if patients were selected using this criterion for bone scanning. Lee and Oesterling [17] concluded that it would be reasonable to omit bone scans in patients with recurrent prostate cancer after radical prostatectomy when the PSA was < 2 ng/mL. However, other studies have shown that PSA (with or without clinical stage and Gleason score) cannot reliably predict bone scan evidence of metastases. This has led some to suggest that bone scans should be used in all patients [18].

NOMOGRAMS AND ARTIFICIAL NEURAL NETWORKS

Currently there are several nomograms that can be used to predict the pathological stage of prostate cancer and survival outcomes. Partin's tables and the associated [19] nomogram use PSA, clinical stage and Gleason score to provide percentage predictions for pathological staging and biochemical recurrence. These predictive values may determine whether a patient is suitable for definitive local, systemic or palliative treatment. However, pathological stage does not always predict clinical outcome and cases should therefore be considered individually. Artificial neural networks incorporate many more variables than do nomograms, and can provide better predictions of pathological staging in prostate cancer [20].

ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES

Plain radiography is cheap, simple, easily available and ideal for evaluating symptomatic sites. However, it is not recommended for screening for bone metastases because of its poor sensitivity; a 50% change in bone density must usually occur before metastases are visible on plain films [2]. CT, although more sensitive than plain radiography, is of limited use because of the length of time and radiation dose that would be needed to screen the whole skeleton [21].

BONE SCINTIGRAPHY

For nearly 30 years bone scintigraphy has been the ‘reference standard’ for detecting skeletal metastases. It is readily available and has a large field of view. Tracer accumulates in normal and abnormal bone depending on the blood flow and degree of bone turnover. Although a bone scan has high sensitivity, it is not specific and a ‘hot spot’ may reflect trauma, tumour, infection, inflammation and even disuse [21]. This can create uncertainty as to the true nature of bone lesions, and may force further investigations such as plain radiography or bone biopsy for equivocal bone scan results.

The UK National Institute of Clinical Excellence (NICE) has published guidelines recommending that routine bone scanning is not necessary in all patients with prostate cancer, and in particular is unlikely to be useful for previously untreated men with a PSA of < 10 ng/mL and Gleason scores of < 8, and who are free from bone pain [3].

There is an ongoing debate as to whether all newly diagnosed patients with prostate carcinoma should routinely have bone scans. By using the NICE guidelines in patients with early prostate cancer, urologists in the UK have been able to reduce healthcare expenditure and waiting times at the cost of missing a few patients with bone metastases. In more advanced disease it may be useful to have a baseline bone scan in all patients for future comparisons, to identify disease recurrence or progression.

NEW METHODS OF DIAGNOSING BONE METASTASES

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES

Recently, advances have led to new and improved forms of radioisotope imaging; single-photon emission CT (SPECT) and positron emission tomography (PET). SPECT and PET have improved both sensitivity and specificity of detecting bone metastases. These isotope scans use fluorodeoxyglucose as a tracer to detect abnormal metabolism in tissues invaded by cancer. For instance, PET scans can detect bone disease well in advance of any scintigraphic evidence, as fluorodeoxyglucose uptake in affected sites [10].

MRI can identify bone metastases at a very early stage, even before there is marked disruption to the homeostatic control of osteoblastic and osteoclastic activity. This is because it can detect bone marrow changes and determine bone marrow cell composition with high anatomical resolution [21]. MRI has developed in recent years and its sensitivity for detecting bone metastases is now close to 100%.

Compared with bone scanning, MRI is simpler and quicker (30 min vs 4 h) for evaluating the axial skeleton, which includes the proximal femora. MRI is more sensitive for early lesions and more specific in differentiating benign from malignant disease than is bone scanning. It has also been shown that asymptomatic solitary peripheral metastases are rare and therefore MRI of the appendicular skeleton is not needed [22]. MRI also avoids exposure to ionising radiation. In terms of running costs, bone scans are still cheaper than MRI, although this may change with the increasing number of MRI scanners being purchased by institutions to cope with the rising demand.

CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES

An accurate way of detecting bone metastases is needed to select patients for radical treatment. There is also evidence that treating bone metastases early may improve the outcome in patients with advanced disease. At present there is no ideal test for detecting bone metastases. Plain radiography lacks sensitivity; bone scanning is more sensitive but is time-consuming and exposes patients to increased radiation, while MRI identifies lesions earlier but is expensive and resources are limited. Stratification of patients into high- and low-risk groups, e.g. by using the NICE guidelines, allows these resources to be used more cost-effectively but inevitably means that some patients with metastases will be missed.

Recently there has been a focus of attention towards biochemical markers released from bone which potentially may allow a simple but rapid method of assessing the risk of bone metastases from prostate cancer.

NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES

Abnormalities of skeletal metabolism result in the release of products of osteoblastic/osteoclastic activity. These may be useful both for diagnosis and monitoring treatment outcome [8]. Biochemical markers of bone disease have been grouped into osteoblastic and osteoclastic markers; a list for both groups is shown in Table 1.

Table 1.  A list of markers of bone metabolism
OsteoblasticOsteoclastic
Alkaline phosphataseHydroxyproline (dialysable)
OsteoclacinHydroxylysine
Hydroxyproline (nondialysable)Acid phosphatase
Aminopropeptide of type 1 procollagen (P1NP)Pyridinoline
Carboxypropeptide of type 1 procollagen (P1CP)Deoxypyridinoline
Type III procollagen

Prostate cancer metastases usually cause osteosclerotic bone lesions, because of the greater bone formation than bone breakdown activity. Several studies have shown that both osteoblastic and osteoclastic markers are useful in predicting and monitoring the tumour burden in bone in patients with prostate cancer. They may also be useful in determining the prognosis in these patients. Two osteoblastic markers, P1NP and P1CP, are particularly promising in prostate cancer.

Collagen for bone formation is formed after the cleavage of aminoterminal and carboxyterminal peptides from procollagen. P1NP is the amino propeptide and P1CP is the carboxy propeptide of type 1 procollagen. Diaz-Martin et al.[23] and Koizumi et al.[24] showed that P1NP is a reliable marker of metastatic bone disease from prostate cancer. This marker outperformed other osteoblastic and osteoclastic markers and had the best correlation with extent of disease.

In another study [25] P1CP was compared with PSA for its reliability as a marker of bone metastatic disease in newly diagnosed prostate cancer; the sensitivity was 83% vs 70%, specificity 96% vs 86% and the overall accuracy 91% vs 81% in favour of P1CP. It is becoming apparent that biochemical markers may have a significant role in assisting with the diagnosis or monitoring of patients with bone metastases from prostate cancer.

POSSIBILITIES FOR THE FUTURE

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES

PSA will always remain an essential tool for urologists in managing prostate cancer. The hope is that this may be combined with the use of biochemical markers such as P1NP to improve the accuracy of prediction of bone metastases. There is now increasing evidence that the previous ‘standard’ management of using bone scans to detect bone metastases may no longer be appropriate, and consideration should be given to substituting this imaging method with PET or MRI, as these approaches become increasingly economical and logistically viable.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. METASTATIC SPREAD AND CHANGES TO BONE BIOLOGY IN PROSTATE CANCER
  4. TREATMENT OPTIONS FOR PROSTATIC BONE METASTASES
  5. ESTABLISHED METHODS FOR PREDICTING BONE METASTASES
  6. ESTABLISHED METHODS IN DIAGNOSING BONE METASTASES
  7. NEW METHODS OF DIAGNOSING BONE METASTASES
  8. CURRENT DILEMMAS AND THE IMPORTANCE OF EARLY PREDICTION AND DETECTION OF BONE METASTASES
  9. NOVEL BIOCHEMICAL MARKERS FOR THE EARLY PREDICTION OF BONE METASTASES
  10. POSSIBILITIES FOR THE FUTURE
  11. CONFLICT OF INTEREST
  12. REFERENCES