Bone metastasis

The primary tumor secretes factors priming the bone and creating a premetastatic niche near highly vascularized trabecular bone.[13] Tumor cells are then attracted to the metastatic niche in the bone marrow, however the characteristics of these niches have yet to be fully elucidated.[13] Initial seeding can occur prior to the discovery of the primary tumor.[13]

The pathogenesis of bone metastases 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.[14] The most common locations of metastases are pelvis, vertebral bodies, ribs and proximal extremities.[14]

Once established, the tumor cells can remain dormant on the bone microenvironment, radiologically undetectable, for many years.[13] The triggers which eventually awaken metastatic tumor cells are an active field of study as they could elucidate mechanisms of controlling dormancy.[13]

Tumor cells secrete factor like Prostaglandin E, TGF-alpha, TGF-beta, TNF, and interleukins which increase bone resorption. The destruction of bone affected by bone metastases are caused by osteoclast-mediated osteolysis. [14] The uncoupled regulation of the osteoclasts and osteoblasts leads to malformation of the bone.[2]

Tumor cells secrete PTHrP which stimulates osteoblasts and bone stromal cells to release RANKL.[13] RANKL binds RANK on osteoclast progenitor cells stimulating them to complete their progression into osteoclasts.[13] Osteoclasts break down bone releasing growth factors (i.e. calcium, IGF-1, and TGF-beta) which further stimulate tumors cells thus feeding forward a vicious cycle.[13] This prominent pathway of bone destruction makes bone-targeting agents an essential tool for treatment of bone metastases.[13]

Tumor cells stimulating bone resorption in a Vicious Cycle. Metastatic tumor cells secrete PTHrP which stimulates Osteoblasts and Stromal bone cells.These cells then stimulate the RANK receptor on osteoclast-precursors transition into bone resorbing osteoclasts by secreting RANKL. Bone contains main growth factors and their release further stimulates metastatic tumor cells.

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.[13] A combination of X-ray, CT and MRI scans provides optimal structural information of the metastases.

A radionuclide bone scan or scintigraphy can also identify bone metastasis. Technetium-99m–labeled bisphosphonate, attaches to calcium at sites of active bone formation.[13] Bone scans are more sensitive and can identify lesions earlier than plain radiographs.[13] But, it cannot identify purely osteolytic lesions and it will also highlight other areas of bone formation like those caused by trauma or inflammation.[13] Additionally, some lesions can be missed in the pelvis due to bladder activity.[13]

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).[10] If a biopsy is indicated, a CT scan is important for localizing the prospective sample tissue.[13]

Unlike diagnostics noted above, an MRI does not need to look for changes in the bone for signs of tumor activity. Instead, it can directly identify cancerous tissue infiltration into the bone.[13] MRIs are good for evaluating bone marrow infiltration and are more sensitive for detecting early spine metastasis.[13]

Positron emission tomography (PET) with fluorine 18–labeled fluorodeoxyglucose ( ¹⁸ F-FDG) are the best diagnostic tool for visualizing the function and activity of bone metastasis.[13] Bone metastases are usually multiple, irregularly distributed foci of increased tracer uptake without relationship to a single anatomic structure.[13] They directly identify tumor cells with significant metabolic rate. PET scans, however, are not regularly used to due high cost and relatively limited accessibility.[13]

Due to the high rate of bone turnover, metabolites are theorized to be capable of detecting bone metastasis.[13] Use of bone markers for detection and screening is an active field of research, though radiographic evidence remains the gold standard.[13] Once the diagnosis of bone metastasis has been established though, bone markers can provide useful prognostic information.[13]

The World Health Organization's pain ladder was designed for the management of cancer-associated pain, and mainly involves various strengths of opioids.

Other treatments include 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]

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]

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-Targeted Agents (BTAs) including Bisphosphonates and Denosumab, can break the vicious cycle of osteoclast-mediated osteolysis.[13] Osteoclast inhibitors, most frequently used in the treatment of osteoporosis, can allow for bone healing and delay complications.[13] BTAs have been shown to decrease the incidence of Skeletal Related Events (SREs) like pathological fractures, thus decreasing the need for surgical intervention or pain medication.[13] These agents have been shown to prevent homing of tumor cells to bone and may maintain the state of dormancy of tumor cells in bone.[13]