Because bone metastases may mimic other diseases that involve skeleton, a patient who has not been diagnosed with cancer and whose primary tumor site has not been identified may present with a fracture. Therefore, it is crucial to identify bone metastases early to ensure appropriate treatment.

Metastatic prostate cancer will be reflected as¹

• Clinical stage: IV (D)
• Gleason classification score: 8 to 10
• Tumor-Node-Metastasis (TNM) prostate classification: M1b

If bone metastases are suspected in a patient with prostate cancer, it is important to confirm the presence and/or extent of the cancer in the bones. This can be accomplished by

• Skeletal radiography¹
  – Identifies the net result of bone resorption and repair
  – Requirement for recognition of destructive lesion in trabecular bone: >1 cm in size and >50% loss in BMD
• Bone scan²
  – Reflects the metabolic reaction of bone to the disease process
  – Focal increase in tracer uptake is often seen before bone destruction can be seen radiologically
• Computed tomography (CT)³
  – Produces images with excellent soft tissue and contrast resolution
  – Shows bony destruction, sclerotic deposits, and soft tissue extension of bone metastases – Used primarily to resolve assessment of patient condition where bone scan is positive and radiograph is negative
• Magnetic resonance imaging (MRI)³
  – Provides multiplanar images
  – Detection of bone metastases depends on differences between tumor tissue and normal bone marrow
  – Metastatic tumor is visualized directly

Prostate-specific antigen (PSA) levels may reflect the extent of disease and the amount of cancer in the prostate gland. They also may be used to monitor the effectiveness of treatment and to help predict disease recurrence. Although not definitive, monitoring this measurement is a standard part of care for the prostate cancer patient. An increasing PSA level can reflect disease progression.

After treatment for any stage of prostate cancer, PSA levels are monitored. PSA velocity, or the rate of rise in PSA concentration, correlates with the risk of cancer.⁴ Higher preoperative PSA velocity has been shown to predict worse outcomes and a significantly higher risk for death from prostate cancer.⁵ PSA doubling time (PSA-DT) was found to be an independent predictor of time to development of metastatic disease; and when considered with other variables, PSA-DT was predictive of the time course of progression to metastasis or death.⁶

According to EAU guidelines⁷:

• Post-radical prostatectomy, 2 consecutive PSA values of ≥0.2 ng/mL define recurrence (international consensus)
• Post-radiation therapy, 3 consecutive increases in PSA define recurrence (ASTRO recommendation)
• Approximately 25% of patients fail primary therapy and develop recurrence within 3 to 5 years

In hormone-refractory prostate cancer, disease progression markers include

• Serum castration testosterone levels <50 ng/dL
• Clinical progression observed in symptoms or physical exam
• Radiographic progression as seen in new lesions or RECIST criteria
• Biochemical progression
  – 2 consecutive rises in PSA, 2 weeks apart, resulting in a 50% increase over nadir or baseline (whichever is higher)
  – Minimum PSA increase (>2 ng/mL) required

Potential osteoblast proliferation and differentiation promoters include⁸

• Endothelin-1
• Transforming growth factor-β (TGF-β)
• Insulinlike growth factor-I (IGF-I)
• Acidic and basic fibroblast growth factors (FGFs)
• Platelet-derived growth factor (PDGF)
• Bone morphogenic proteins (BMPs)
• Prostate-specific antigen (PSA) (?)

Osteoclast promoters and inhibitors include⁸

• Receptor activator of nuclear factor-kB (RANK)
• RANK ligand (RANKL)
• Osteoprotegerin (OPG)
• Parathyroid hormone (PTH) and PTH-related peptide (PTHrP)

Osteoporosis (bone loss), a disease that is common in older men, may result from prostate cancer treatment, among other causes. The development of osteoporosis is related to changes in bone mineral density (BMD). Preserving bone health in order to prevent skeletal-related complications and preserve an acceptable quality of life is an important part of therapy in patients with metastatic prostate cancer.⁹

BMD can be determined by several noninvasive methods, including⁹

• Dual-energy x-ray absorptiometry (DEXA)
  – Method of choice
  – Measures BMD easily and precisely
  – Measures BMD at multiple skeletal sites with minimal radiation exposure
     - Posterioranterior lumbar spine BMD for evaluating efficacy of treatment
     - Hip BMD for predicting fractures
  – Limitations in older men
• Quantitative CT scan
  – More sensitive but less precise than DEXA in men
  – Measures trabecular BMD and avoids confounding effects of osteoarthritis
• Ultrasound measurements of heel, finger, tibia, or patella
  – Inexpensive and portable method but relatively imprecise
  – Skeletal sites evaluated are unresponsive to treatment

Secondary causes of bone loss should be considered in men with an established diagnosis of osteoporosis. Laboratory tests are available to help exclude conditions of hypothyroidism, vitamin D deficiency, and renal or liver disease.⁹

Measurement of biochemical markers of bone resorption and bone formation in serum and urine can complement BMD measurements. For example,

• Markers of bone turnover⁹
  – May provide an early indication of response to treatment
• High levels of bone turnover⁹
  – Are associated with greater rates of bone loss
  – May predict fracture risk

However, biochemical markers should not be used in place of BMD measurements. According to a definition based on World Health Organization recommendations, osteoporosis in men exists when the BMD T-score by DEXA is >2.5 standard deviations below the peak young normal mean reference range (T-score < -2.5). Standardized software derived from reference data bases for healthy Caucasian men ages 20 to 40 years should be used to obtain accurate T-score calculations.¹⁰

1.	Edelstein GA, Gillespie PJ, Grebbel FS. The radiological demonstration of osseous metastases: experimental observations. Clin Radiol. 1967;18:158.
2.	Fogelman I, Coleman RE. The bone scan and breast cancer. In: Freeman L, Weissman H, eds. Nuclear Medicine Annual. New York, NY: Raven Press; 1988:1.
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4.	Carter HB, Pearson JD. Prostate-specific antigen velocity and repeated measures of prostate-specific antigen. Urol Clin North Am. 1997;24:333-338.
5.	D'Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. NEJM. 2004;351:125-135.
6.	Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597.
7.	European Association of Urology. Guidelines on prostate cancer. February 2003. Update. (ISBN 90-70244-06-3). Available at http://www.uroweb.org/index.php?structure_id=140. Accessed December 6, 2004.
8.	Gandhok N, Sartor O. In: Klein EA, ed. Clinical Urology: Management of Prostate Cancer. 2nd ed. Totowa, NJ: Humana Press Inc.
9.	Smith MR. Diagnosis and management of treatment-related osteoporosis in men with prostate cancer. Cancer. 2003;97(suppl 3):789-795.
10.	Diamond TH, Higano CS, Smith MR. Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy. Cancer. 2004;100:892-899.