Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis

INTRODUCTION — The spectrum of the clinical manifestations of prostate cancer has changed substantially since the introduction of prostate-specific antigen (PSA) screening, with a higher percentage of males now having localized disease at presentation. However, metastatic prostate cancer remains an important clinical problem, both in terms of the number of affected males and its impact on quality of life.

The bones of the axial skeleton are the predominant site of metastasis in most males with metastatic prostate cancer (image 1), and these lesions can cause pain, debility, and/or functional impairment in addition to contributing to mortality. The clinical manifestations and diagnostic assessment of bone metastases in males with prostate cancer are reviewed here.

An overview of bone metastases is presented separately, as is a discussion of the management of patients with prostate cancer bone metastases. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults" and "Bone metastases in advanced prostate cancer: Management".)

PATHOPHYSIOLOGY — Malignant cells are widely disseminated in males with advanced prostate cancer. However, metastases preferentially develop in the bones of the axial skeleton, where red marrow is most abundant. The reasons for this pattern of metastasis are unclear, but the leading hypothesis focuses on symbiotic interactions between prostate cancer cells and bone stromal cells, such as osteoblasts, osteoclasts, and fibroblasts.

The bone metastases in males with prostate cancer are usually osteoblastic (ie, characterized by new bone formation). However, increases in bone resorption have been consistently demonstrated histologically and biochemically even in those with osteoblastic metastases. Bone destruction is an important factor in the etiology of pain and other complications due to bone metastases, although it is unclear if such bone destruction precedes the development of osteoblastic metastases or is a consequence of increased bone formation.

The mechanisms by which prostate cancer tumor cells induce osteoblastic changes are unclear but are thought to involve excess activation of osteoblast mitogens, some of which are derived from bone stroma (insulin-like growth factors, transforming growth factor beta, bone-morphogenic proteins, proteases, fibroblast growth factors, endothelin, other soluble factors) and others from the prostate cancer itself. A vicious cycle, with positive feedback between prostate cancer cells and bone stroma, has been proposed.

CLINICAL MANIFESTATIONS — Bone is the predominant site of disseminated prostate cancer in males who present with or subsequently develop metastatic disease. Although bone metastases are often asymptomatic initially, patients can eventually develop complications that require treatment; these skeletal-related complications include pain requiring irradiation, pathologic fractures, spinal cord compression, surgery to bone, and occasionally, abnormalities of calcium metabolism.

Pain — Pain is the most common manifestation of bone metastases. Pain from bone metastases is typically insidious at onset and slowly increases in severity over weeks to months. However, there are exceptions, such as a pathologic fracture or the sudden onset of back pain that accompanies the collapse of a cancer-containing vertebral body.

Although bone pain due to metastasis is commonly described as aching (such as a toothache), nerve root entrapment, a common complication associated with vertebral metastases, may cause a burning and/or radiating type of pain. It is common that males with prostate cancer attribute their pain to a nonmalignant cause and clinicians need to be aware that bone pain needs investigation despite patients history of other causes.

Pain located distal to the knees or elbows is less likely to be malignant than that located proximally or centrally because cancers typically spread to bone areas with active marrow function. Arthritic pain is more likely to localize to joints than pain from bone metastases, but history alone cannot reliably distinguish the two. (See "Assessment of cancer pain".)

Uncontrolled pain due to bone metastases results in unnecessary suffering, fractures, decreased ability to cope with illness, and interference with activities of daily living, and it can necessitate extended or repeat hospital admissions. Uncontrolled pain may also delay or disrupt anticancer treatment, compromising its effectiveness. (See "Bone metastases in advanced prostate cancer: Management" and "Cancer pain management: General principles and risk management for patients receiving opioids".)

Pathologic fractures — Pathologic fractures are an important but relatively uncommon clinical manifestation of bone metastases from prostate cancer under most circumstances (image 2). Although prostate cancer bone metastases are typically osteoblastic, the structure of osteoblastic bone may be abnormal, and there is usually significant destruction of normal bone cortex (image 3), which leads to bone strength being suboptimal.

Systemic treatment with androgen deprivation therapy (ADT), steroids, or newer drugs, such as abiraterone, can contribute to osteoporosis, which increases the risk of fractures. Osteoporotic fractures need to be distinguished from the pathologic fractures caused by bone metastasis. (See "Side effects of androgen deprivation therapy", section on 'Osteoporosis and bone fractures'.)

Spinal cord compression — Vertebral metastases are particularly common in males with advanced prostate cancer. Such metastases can be associated with spinal cord compression and the possibility of severe neurologic deficits.

Pain is usually the first symptom of spinal cord compression, and this generally precedes the development of other symptoms by weeks or even months. A focused neurologic examination is required in males with back pain because of the risk of epidural spinal cord compression. Symptoms occurring later can include motor weakness, sensory findings, bowel and bladder dysfunction, and ataxia. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Clinical features'.)

Early recognition of the clinical features of epidural spinal cord compression, followed by prompt treatment, is critical in minimizing the neurologic deficits associated with this complication. (See "Treatment and prognosis of neoplastic epidural spinal cord compression", section on 'Symptomatic and preventive care'.)

Hypercalcemia and hypocalcemia — Hypercalcemia is uncommon in males with advanced prostate cancer compared with other malignancies where osteolytic disease is more common than osteoblastic disease. Hypocalcemia is more frequent but is generally asymptomatic. Hypocalcemia is typically due to treatment with bone-modifying agents (bisphosphonates, denosumab). (See "Hypercalcemia of malignancy: Mechanisms" and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Hypocalcemia and other electrolyte abnormalities'.)

Other laboratory abnormalities — The most common abnormal laboratory findings observed in males with bone metastatic prostate cancer are an elevated serum prostate-specific antigen (PSA) level, an elevation in serum alkaline phosphatase, and anemia. However, these laboratory abnormalities are not useful in either establishing or ruling out the diagnosis of bone metastasis in males with prostate cancer:

●The serum PSA is typically >10 ng/mL in males with metastatic well-differentiated or moderately differentiated tumors [1]. However, poorly differentiated prostate cancers with a high Gleason score produce little PSA, and lower or even normal PSA values do not exclude bone metastases. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Aggressive prostate cancer variants'.)

●Osteoblastic metastases are commonly, but not inevitably, accompanied by elevations in markers of bone turnover (eg, serum bone-specific alkaline phosphatase, urinary hydroxyproline, urinary deoxypyridinoline). However, these are not routinely measured clinically. Although serial measurement of biochemical bone markers may not be useful in males with metastatic prostate cancer [2,3], a significant decline in bone-derived alkaline phosphatase is a reasonably reliable indicator of a favorable therapeutic response. In addition, high levels of bone-associated alkaline phosphatase are associated with a poor prognosis and a greater risk of adverse skeletal outcomes [2,4,5]. Because elevated serum alkaline phosphatase can be derived from bone or the liver, further evaluation to distinguish the site of origin may be warranted. In the vast majority of males with prostate cancer who have an elevated serum alkaline phosphatase, the abnormality is caused by bone metastases. (See "Bone physiology and biochemical markers of bone turnover" and "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated alkaline phosphatase'.)

●Anemia is common and typically proportional to the extent of bone involvement. However, anemia may also be caused by a variety of factors, including ADT [6], radiation, systemic cytotoxic chemotherapy, disseminated intravascular coagulation, or a combination of poorly defined tumor-related factors.

Frequency of skeletal-related events — The risk of progression to metastatic disease at presentation, and hence the risk of subsequently developing bone metastases, is a function of multiple factors, which are incorporated into the American Joint Committee on Cancer (AJCC) staging system. In a prospective study looking at the risk of future bone metastases, the most important factors for males with castration-resistant prostate cancer and nonmetastatic disease were a rapidly rising PSA and a baseline PSA of >13 ng/mL [7]. (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

The frequency of skeletal-related complications rises progressively with more extensive disease. The incidence of such events in males with castration-resistant prostate cancer who have developed bone metastases was illustrated by a trial in which 1901 patients were randomly assigned to osteoclast inhibition with either zoledronic acid or denosumab [8]. The median times to first skeletal-related event were 17 and 21 months, respectively. For the entire cohort, the frequencies of bone pain requiring radiation therapy, pathologic fracture, and spinal cord compression were 20, 15, and 3 percent, respectively. In these studies, the pathologic fracture rates were assessed by skeletal surveys rather than symptoms.

EVALUATION AND DIAGNOSIS — Pain is the most common manifestation of bone metastases. Prostate cancer patients with bone pain that cannot be definitively attributed to another condition should be evaluated for bone metastases. Pathologic fracture and spinal cord compression are less common and usually occur in the context of a patient with known bone metastases.

Asymptomatic patients — Routine evaluation for occult bone metastases in asymptomatic patients is not indicated in many cases at initial diagnosis or at the first evidence of a rising prostate-specific antigen (PSA) following definitive therapy because of the low incidence of metastatic disease. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Evaluation for distant metastases' and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation".)

Symptomatic patients — The development or worsening of bone pain, or a sustained rise in PSA or alkaline phosphatase is the primary indication for evaluation for bone metastases, but it should not automatically be interpreted as being due to bone metastasis. Worsening pain from a wide range of nonmalignant conditions (eg, arthritis, disc injury, musculoskeletal discomfort related to physical exertion) and treatment-related complications (eg, nerve root compression from vertebral body collapse due to treatment-related osteoporosis) needs to be considered in the differential diagnosis.

The choice of imaging procedure is guided by the clinical setting:

●Radionuclide bone scan – Technetium-99 with methylene diphosphonate (99Tc-MDP) radionuclide bone scans are typically used as the first test for evaluation of a patient with suspected bone metastases but without symptoms or physical findings suggesting a pathologic fracture or incipient spinal cord compression. Bone scans preferentially detect osteoblastic (as compared with osteolytic) metastases and are the most often used imaging modality to assess the presence, number, and anatomic distribution of bone metastases in males with prostate cancer (image 4).

Bone scans are most effective at detecting osteoblastic metastases and those with mixed blastic and lytic components. Occasional patients have predominantly osteolytic disease, and a negative bone scan does not rule out bone metastases. Plain radiography, computed tomography (CT), or magnetic resonance imaging (MRI) is indicated if bone metastases are suspected following a negative bone scan.

Sodium fluoride-18 (Na18F) positron emission tomography (PET) scan is a more sensitive method of detecting suspected bone metastases, but it is not more specific than scanning with 99Tc-MDP [9]. However, the clinical implications of a 99Tc-MDP and Na18F scan are not necessarily the same since Na18F scans are susceptible to false positives because the uptake is not cancer specific [10]. More recently PET scans using prostate-specific membrane antigen radiotracers have been shown to be effective and sensitive in detecting a variety of metastatic sites, including bone. These are discussed separately. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Evaluation for distant metastases'.)

●Plain radiographs – Plain radiographs are more specific but less sensitive than bone scans. Plain films are the preferred initial imaging procedure when a pathologic fracture or compression fracture is suspected.

Benign lesions can cause increased uptake on bone scan, and plain radiographic imaging may also be indicated to confirm abnormal or equivocal findings from a radionuclide bone scan. Plain films may also be useful for diagnosing treatment-related osteoporosis and osteoporotic fractures.

●Magnetic resonance imaging – Urgent MRI is indicated for patients with a suspected spinal cord compression based on symptoms or physical findings. MRI can be useful for distinguishing equivocal lesions found on radionuclide bone scans from other abnormalities. (See 'Spinal cord compression' above and "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Magnetic resonance imaging of the spine'.)

Histologic diagnosis — Regardless of the clinical presentation, suspected metastatic disease based on imaging studies should be histologically confirmed (at least on the first presentation with suspected metastases) by an image-guided biopsy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neoplastic epidural spinal cord compression" and "Society guideline links: Management of bone metastases in solid tumors".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Bone metastases (The Basics)")

SUMMARY

●Clinical manifestations

•Bone is the predominant site of disseminated disease in males with prostate cancer who present with or subsequently develop metastatic disease. Pain is the most common manifestation of bone metastases. Pain from bone metastases is typically insidious at onset and slowly increases in severity over weeks to months. (See 'Pain' above.)

•Pathologic fractures are an important clinical manifestation of bone metastases from prostate cancer. Although prostate cancer bone metastases are typically osteoblastic, the structure of osteoblastic bone may be abnormal, and there is often a significant osteolytic component. (See 'Pathologic fractures' above.)

•Vertebral metastases are particularly common in males with advanced prostate cancer. Such metastases can cause spinal cord compression and severe neurologic deficits. Early recognition of the clinical features of epidural spinal cord compression, followed by prompt treatment, is the most important step in minimizing the neurologic deficits associated with this complication. (See 'Spinal cord compression' above and "Treatment and prognosis of neoplastic epidural spinal cord compression", section on 'Symptomatic and preventive care'.)

●Diagnosis – The diagnosis of bone metastases is based on imaging findings. The choice of imaging procedure is based on the clinical setting:

•Routine imaging is not indicated in patients at low risk for the development of bone metastases. (See 'Asymptomatic patients' above and "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Diagnosis' and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation".)

•Technetium-99 with methylene diphosphonate radionuclide bone scan is the current preferred imaging modality for the overall assessment of the number and location of bone metastases. (See 'Pain' above and 'Symptomatic patients' above.)

•Plain radiographs are particularly useful for the initial assessment of patients thought to have a pathologic fracture. They are also indicated for the assessment of equivocal findings on bone scan and for patients with purely osteolytic disease. CT scans may also be helpful to assess bone detail. (See 'Pathologic fractures' above and 'Symptomatic patients' above.)

•MRI is required for prompt evaluation of patients with signs or symptoms suggestive of spinal cord compression. (See 'Spinal cord compression' above and "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Magnetic resonance imaging of the spine'.)

ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.