Bone metastases


Release osteoclast activators and substances that accelerate bone resorption.

Disturbances associated with increased turnover, focal imbalance at remodeling sites and uncoupling of bone resorption and bone formation.

Reported to occur in approximately 50% of patients with metastatic cancer, but multiple , breast, prostate, lung kidney and thyroid carcinoma are more frequently associated with clinically symptomatic bone lesions.

Approximately 80% of patients with breast cancer, prostate cancer, and lung cancer develop bone metastases.

Breast and prostate cancer are responsible for more than 80% of cases of symptomatic bone metastases in oncologic practices.

The term metastatic bone disease includes bone marrow and bone metastasis regardless of tumor histology.

Bone is almost always affected in multiple myeloma and metastatic breast cancer and prostate cancer, approximately 70% of patients may have been evidence of metastatic bone disease.

Bone is the most frequent side of distant relapse for breast cancer, occurring in approximately 40% of all first distant recurrences.

Up to 80% of patients with metastatic breast cancer will develop bone metastases during their disease course.

Bone metastases disrupt normal bone structure and function and increased risk of skeletal events, including pathologic fractures, hypercalcemia of malignancy, spinal cord compression, and the need for palliative radiation or surgical intervention.

Bone metastasis may lead to pain and to disrupted bone marrow function.

Commonly affect the axial skeleton and hematogenous spread is most likely route, caused by venous drainage from visceral organs directly into axial bones.

Autopsy studies reveal that venous blood from the breasts and pelvic organs flow into the vena cava and also into the vertebral venous plexus vessels (Batson’s) extending from the pelvis throughout the epidural and perivertebral veins.

Develop via a multistep process with primary tumor cells entering the circulating systemic circulation and adhering to the vascular endothelial and eventually invading the skeletal stroma.

Such hematogenous routes may explain the high proclivity of breast and prostate cancer to involve the axial skeleton.

Tumor cells that metastasize to bone are able to exploit the microenvironment to utilize bone physiology to further their own growth and cause skeletal damage.

Release of growth factors, cytokines and calcium by bone during resorption supports survival and proliferation of infiltrated cancer cells.

Cancer cells secrete growth factors and cytokines, increasing the synthesis and maturation of osteoblasts, leading to an increase in RANK ligand (RANKL).

RANKL contributes to an increase in osteoclast formation, function and survival enhancing bone resorption: Causing the cycle of cancer induced bone destruction and tumor cell growth.

Because skeletal integrity is maintained by bone remodeling with resorption by osteoclasts and replacement of new bone by osteoblasts, the bone is a favorable environment for tumor survival and growth.

Metastatic cancer cells in bone stimulate osteoblasts to release receptor activator of nuclear factor kB ligand (RANKL), which binds to its receptor RANK, on both precursor and mature osteoclasts: increased osteoclastic bone resorption can lead to release of bone derived growth factors that provide a fertile environment for survival and growth of adjacent cancer cells.

Tumor cells can reside in the bone microenvironment, possibly for years, before they become active in bone metastases.

It is theorized that a “viscous cycle” exists that cytokines, chemokines and hormones released from the destructive process of metastases and subsequently amplifies growth of the tumor.

Involve detachment of cancer cells from primary organ, invasion into adjacent tissue, extravasation into the tumor vasculature and general circulation system in response to proangiogenic factors, followed by chemotaxis to bone.

Metastases to bone involve attachment of cancer cells to the basement through through cell adhesion molecules laminin and E-cadhedrin, degradation of the extracellular matrix by proteolytic enzymes, and chemotactic migration through the basement membrane.

Cancer cells produce cytokines and growth factors that impact osteoclastic bone resorption.

Most of the osteolytic factors secreted by tumor cells act via the osteoclast differentiation factor RANKL, which in turn increases osteoclast formation and bone resorption.

Increased resorption of bone from the matrix releases growth factors that increases tumor growth initiating a viscous cycle between tumor stimulation of bone destruction and tumor growth.

Prior to the advent of bone targeted treatments breast cancer patients with bone metastasis had an average of 3.7 skeletal related events per year, one every 3 to 4 months.

Bisphosphonates int2242upt the viscous cycle of bone microenvironment by inhibiting osteoclast mediated bone resorption and inhibits the effects of bone derived growth factors.

Inhibitors of RANKL are thought to block osteoclast formation.

Metastatic cancer cells, osteoblasts, osteoclasts and bone matrix are a source of growth factors.

Cancer cells secrete osteoblastic and osteolytic factors.

Osteoblastic factors include: ET-1, AM, VEGF, PDGF, and CCNs stimulate osteoblast proliferation, differentiation and the secretion of more growth factors which are deposited into the bone matrix, enriching the local tumor cell microenvironment.

Tumor stem cells home to bone marrow via receptors such as CXCR-4 to hematopoietic niches with high levels of stromal derived factor 1 (SDF-1).

The RANK receptor is expressed on cancer cells and plays a role in the homing process of tumors cells.

RANK L, the RANK ligand, is expressed in the bone marrow microenvironment by stromal cells and immature osteoblasts and tumor cells from breast and other cancers also express RANK and can utilize this receptor to home to bone.

Parathyroid hormone related protein (PTHrP) plays a significant role in bone metastases in breast cancer and prostate cancer via its induction of RANK L.

Tumor cells produce factors that increase osteoclast precursors by stimulating interleukins 6, 8, 11, tumor necrosis factor alpha, granulocyte macrophage colony stimulating factor, macrophage inflammatory protein-1 alpha, and macrophage inflammatory protein -1.

Micrometastases to bone probably occurs early in the malignant process with 71% of patients have detectable prostate cancer cell in their peripheral blood prior to undergoing radical prostatectomy (Vessela).

Treatment with bone-protecting agents (BPAs) zoledronic acid or denosumab entirely eliminated the risk of fracture as seen in a study of men with metastatic castration-resistant prostate cancer (CRPC) treated with enzalutamide alone or in combination with radium-223.

Many patients with breast cancer have micrometastases to bone at the time of diagnosis (Lang).

More than 90% of tumors of the bone are metastatic.

Affects more than 400,000 individuals in the U.S. annually, more than any other site of metastases.

Up to 80% of patients who die with cancer have bone metastases.

First manifestation of lung cancer in 2.3% of cases.

Approximately 50% of patients with lung cancer present for the first time with signs or symptoms of bone metastases.

Pain secondary to metastases often worse at night.

Bone metastases are the most common cause of chronic pain in cancer patients.

Bone metastases pain may be due to stretching of the periosteum or nerve entrapment due to tumor, fractures caused by osteolytic bone destruction, and local micro environment which activates nociceptor signaling pathways.

Patients with bone metastases who experience a skeletal related event are at higher risk for developing a subsequent skeletal related event.

Pain initially is dull and of low intensity and progresses to chronic pain with intermittent severe episodes of acute pain.

Pain mechanisms include tumor induced cytokines, nerve injury, infiltration of bone trabeculae and matrix.

The peripheral nerve endings triggered by substances produced by tumor cells, including prostaglandin E, interleukins, substance P, transforming growth factor, tumor necrosis factor cause allodynia and hyperalgesia.

Occurs secondary to hematogeous spread.

Approximately 60% of breast cancer patients with osseous metastases develop pathologic fractures within 11 months after the finding of bone lesions.

The most catastrophic outcome with metastatic bone disease is spinal cord compression due to collapse of vertebrate or extension of such bone metastasis to the epidural space leading to incontinence, paralysis and long-term care.

20% of patients with breast cancer and bone metastases develop hypercalcemia after a median of 14 months.

The most frequent imaging technique for detecting bone metastases is the bone scan.

CT scans are more sensitive than conventional radiography for detecting bone destruction.

MRI highly sensitive for detection for bone metastases because it can detect bone marrow abnormalities.

Following surgical repair of long bone metastases radiation should be given postoperatively as it is associated with improved level of function compared to surgery alone.

Prophylactic surgical management is recommended for long bones if patients have persistent pain after radiation therapy or have a lytic lesion circumferentially involving more than 50% of the cortex.

Median survival after the development of bone metastases ranges from 6-48 months depending on the primary tumor type.

Pain mediated by pain receptors in the endosteum by inflammatory and cellular mediators, microfractures and stretching of the periosteum.

Pain postulated to be due to chemical mediators that can trigger nociceptors in periosteum, or bone marrow, nociceptor sensitization, CNS excitation and inhibition, and pressure on local peripheral nerves.

Skeletal related events occur in 46%-68% of patients with bone metastases from solid tumors.

Patients may experience multiple skeletal related events, and the risk increases after the first event.

Skeletal related events include: pathologic bone fractures, spinal cord compressio, requirement for surgery or radiotherapy and hypercalcemia.

Skeletal related events impair physical and emotional well being and are associated with decreased survival.

Skeletal related events may occur every 3-4 months.

Management includes: pain medications, radiation, and surgical procedures that may be required to relieve pain, preserve function, and/or maintain skeletal integrity.

Bisphosphonate therapy decreases skeletal related events by up to 50% and slows the rate of development os such events.

Bisphosphonate therapy decreases skeletal related events by up to 50% and slows the rate of development os such events.

Approximately 20% of patients, despite bisphosphonates, will still have elevated bone resorption markers.

Palliative radiation therapy for such lesions is 30 grays in 10 fractions as standard treatment.

Similar outcomes for radiation therapy for bone metastases is 30 grays 8 Gy in 1 fraction and 20 Gy in 5 fractions.

Single fraction stereotactic radiation therapy is not inferior to Standish dose multi fraction radiation therapy in terms of pain control and local disease control.: Its suggested SBRT should be the standard of care in patients with excellent performance status, longer life expectancy, and limited bone metastases (Nguyen Q).

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