Bone metastasis

Many cancers spread to bone, but not all bones are implicated in cancerous metastasis. The microenvironment of differing bone types is thought to play a role in its predisposition to tumor seeding.[13] For example, trabecular bone rich in red marrow and bone subject to frequent turnover are more likely to be seeded[13] at premetastatic niches formed by interactions between cancerous cells and bone substrate[14] Tumor cells are then attracted to the metastatic niche in the bone. However, the characteristics of these niches have yet to be fully elucidated.[14] Initial seeding can occur prior to the discovery of the primary tumor.[14]

The pathogenesis of bone metastasis via the vasculature is hypothesized to be related to the Batson vertebral vein plexus, a longitudinal valveless system connected to the breast, lung, kidney, thyroid, and prostate gland that extends from the sacrum to the skull.[15] The most common locations of metastases are the pelvis, vertebral bodies, ribs and ends of long bones.[15]

Once established, the tumor cells can remain dormant on the bone microenvironment, radiologically undetectable, for many years.[14] The triggers which eventually awaken metastatic tumor cells are an active field of study as they could elucidate mechanisms of controlling dormancy.[14]

Tumor cells may have paraneoplastic effects, such as via the secretion of Prostaglandin E, TGF-alpha, TGF-beta, TNF, and interleukins to increase bone resorption. The destruction of bone affected by bone metastases are caused by osteoclast-mediated osteolysis.[15] The uncoupled regulation of osteoclasts and osteoblasts leads to malformation of the bone.[2] Lytic bone lesions may also lead to the pathogenesis of hypercalcemia in cancers that have spread to bone[16]

A plain film x-ray of the entire body can identify bone metastasis. However, the sclerotic or osteolytic lesions must be at least 1 cm in diameter.[14] A combination of X-ray, CT and MRI scans may be most sensitive in the diagnosis of cancerous bone metastasis.[14]

A radionuclide bone scan or scintigraphy can identify bone metastasis. Technetium-99m–labeled bisphosphonate attaches to calcium at sites of active bone formation.[14] Bone scans are more sensitive and can identify lesions earlier than plain radiographs.[14] However, these methods are less effective at identifying purely osteolytic lesions and will also highlight other areas of bone formation, such as those caused by trauma or inflammation unrelated to cancer.[14] Additionally, bladder activity may mask the detection of certain pelvic lesions.[14]

A CT scan can detect bone metastases before they present with symptoms in patients diagnosed with tumors that are high-risk for spread to the bone. 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).[10] If a biopsy is indicated, a CT scan is often used to localize the lesion before biopsy.[14]

MRIs can be used to detect bone metastasis with a sensitivity of 82-100% and a specificity of 73-100%.

Positron emission tomography (PET) with fluorine 18–labeled fluorodeoxyglucose ( ¹⁸ F-FDG) is a powerful diagnostic tool to visualize the activity of bone metastasis.[14] Bone metastases on PET scan are usually multiple, irregularly distributed foci of increased tracer uptake without relationship to a single anatomic structure.[14] A PET scan can directly identify tumor cells with significant metabolic rate. However, it is a costly procedure and device availability may be limited.[14]

Due to the high rate of bone turnover, metabolites are theorized to be capable of detecting bone metastasis.[14] Use of bone markers for detection and screening is an active field of research, though radiographic evidence remains the gold standard.[14] However, once the presence of a bone metastasis has been established, tumor metabolic markers can provide useful diagnostic and prognostic information.[14]

The World Health Organization's pain ladder was designed for the management of cancer-associated pain. The original ladder details the management of pain using a sequence of analgesic medications, starting with non-steroidal anti-inflammatory medications and progressing to weak and strong opioids[17]

Other treatments include corticosteroids, radiotherapy, and radionucleotides.[2] Percutaneous osteoplasty involves the use of bone cement to reduce pain and improve mobility.[18] In palliative therapy, the main options are external radiation and radiopharmaceuticals.[19]

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.[20] 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.[21][22] 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.[23]

A Cochrane review of calcitonin for the treatment of metastatic bone pain suggests calcitonin yields no significant benefit in the reduction of bone pain or improvements in quality of life.[24]

Bone-Targeted Agents (BTAs) including Bisphosphonates and Denosumab, can interrupt osteoclast-mediated osteolysis.[14] Osteoclast inhibitors, most frequently used in the treatment of osteoporosis, can allow for bone healing and delay complications.[14] BTAs have been shown to decrease the incidence of Skeletal Related Events (SREs) like pathological fractures, thereby decreasing the need for surgical intervention or pain medication.[14]