Bone metastasis

Under normal conditions, bone undergoes a continuous remodeling through osteoclast-mediated bone resorption and osteoblast-mediated bone deposition.[3] These processes are normally tightly regulated within bone to maintain bone structure and calcium homeostasis in the body. Disregulation of these processes by tumor cells leads to either osteoblastic or osteolytic lesions, reflective of the underlying mechanism of development.[3] Typically, osteolytic metastases are more aggressive than osteoblastic metastases, which have a slower course. Regardless of the phenotype, though, bone metastases show osteoclast proliferation and hypertrophy.[4]

Primary tumors

• Osteoblastic lesions[5]
  • Prostate cancer
  • Carcinoid
  • Small cell lung cancer
  • Hodgkin lymphoma
  • Medulloblastoma
• Osteolytic lesions[5]
  • Non-small cell lung cancer
  • Thyroid cancer
  • Kidney cancer
  • Multiple myeloma
  • Melanoma
  • Non-Hodgkin lymphoma
  • Langerhans cell histiocytosis
• Mixed lesions[5]
  • Breast cancer
  • Testicular cancer
  • Ovarian cancer
  • Gastrointestinal cancers
  • Squamous cell skin cancers

Bone metastases are a major clinical concern that can cause severe pain, bone fractures, spinal cord compression, hypercalcemia, anemia, spinal instability, decreased mobility, and rapid degradation in the quality of life for patients.[6][7] Patients have described the pain as a dull ache that grows worse over time, with intermittent periods of sharp, jagged pain.[2] Even under controlled pain management, these periods of breakthrough pain can occur rapidly, without warning, several times a day.[8] Pain may be worse at night and partially relieved by activity.[9] Metastases to weightbearing bones may become symptomatic early in the course of disease as compared to metastases to the flat bones of the rib or sternum.[9]

Effects of bone metastasis

• severe pain
• bone fractures
• spinal cord compression
• hypercalcemia
• anemia
• spinal instability
• decreased mobility

Causes of symptoms

Sclerotic breast cancer metastases in the pelvis.

Acidosis

Acidosis is the increased acidity in a given location, whether it is blood, urine, or tissues. Osteoclasts generate extracellular protons, lowering the pH of the extracellular matrix (ECM) around the osteoclast to approximately 4.5.[10] Nociceptors in the bone trigger a pain response in the brain in response to this acidosis.[11] It is thought that this is the primary source of the dull, chronic pain experienced by patients with bone metastasis.

Bone restructuring

The uncoupled regulation of the osteoclasts and osteoblasts leads to malformation of the bone.[2] Malformed bones are unable to withstand the normal mechanical stresses placed on them in day-to-day activity, leading to fractures, spinal compression, and spinal instability. Malformed bones may also mechanically trigger pain receptors both within the bone and in the surrounding tissue.

Main sites of metastases for some common cancer types, with lung and breast routes to bones shown at shoulder level. Prostate cancer, the third major source,[3] is not shown because of female model. Primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases".[12]

CT scan in the coronal plane of bone metastases of the hip bone, in a 60-year-old woman with parotid gland cancer. The more affected side is very irregular and sclerotic (visible as brighter in this presentation).

Bone is the third most common location for metastasis, after the lung and liver.[13] While any type of cancer is capable of forming metastatic tumors within bone, the microenvironment of the marrow tends to favor particular types of cancer, including prostate, breast, and lung cancers.[3] Particularly in prostate cancer, bone metastases tend to be the only site of metastasis.[2] The most common sites of bone metastases are the spine, pelvis, ribs, skull, and proximal femur.[9]

Common primary tumors

• Breast cancer
• Prostate cancer
• Lung cancer

A CT scan can detect bone metastases before becoming symptomatic in patients diagnosed with tumors with risk of spread to the bones. Even sclerotic bone metastases are generally less radiodense than enostoses, and it has been suggested that bone metastasis should be the favored diagnosis between the two for bone lesions lower than a cutoff of 1060 Hounsfield units (HU).[14]

The goals of the treatment for bone metastases include pain control, prevention and treatment of fractures, maintenance of patient function, and local tumor control.[9] Treatment options are determined by multiple factors, including performance status, life expectancy, impact on quality of life, and overall status of clinical disease.

Pain management

The World Health Organization's pain ladder was designed for the management of cancer-associated pain, and mainly involves various strength of opioids. Mild pain or breakthrough pain may be treated with nonsteroidal anti-inflammatory drugs.

Other treatments include bisphosphonates, corticosteroids, radiotherapy, and radionucleotides.[2] Percutaneous osteoplasty involves the use of bone cement to reduce pain and improve mobility.[15] In palliative therapy, the main options are external radiation and radiopharmaceuticals.[16] High-intensity focused ultrasound (HIFU) has CE approval for palliative care for bone metastasis, though treatments are still in investigatory phases as more information is needed to study effectiveness in order to obtain full approval in countries such as the USA.

Thermal ablation techniques are increasingly being used in the palliative treatment of painful metastatic bone disease. Although the majority of patients experience complete or partial relief of pain following external radiation therapy, the effect is not immediate and has been shown in some studies to be transient in more than half of patients.[17] For patients who are not eligible or do not respond to traditional therapies ( i.e. radiation therapy, chemotherapy, palliative surgery, bisphosphonates or analgesic medications), thermal ablation techniques have been explored as alternatives for pain reduction. Several multi-center clinical trials studying the efficacy of radiofrequency ablation in the treatment of moderate to severe pain in patients with metastatic bone disease have shown significant decreases in patient reported pain after treatment.[18][19] These studies are limited, however, to patients with one or two metastatic sites; pain from multiple tumors can be difficult to localize for directed therapy. More recently, cryoablation has also been explored as a potentially effective alternative as the area of destruction created by this technique can be monitored more effectively by CT than radiofrequency ablation, a potential advantage when treating tumors adjacent to critical structures.[20]

Monthly injections of radium-223 chloride (as Xofigo, formerly called Alpharadin) have been approved by the FDA in May 2013 for castration-resistant prostate cancer (CRPC) with bone metastases.

A Cochrane review of calcitonin for the treatment of metastatic bone pain indicated no benefit in reduction of bone pain, complications, or quality of life.[21]

• Bone tumor