Bone

What are bone metastases?

Bone metastases are a common complication in patients with advanced cancer.

The skeleton is more often affected in patients with:

• metastatic breast cancer,
• Prostate cancer.

This is a secondary neoplasm that develops in another organ and then spreads to bone tissue.
The spread takes place via:

• blood circulation,
• the lymphatic system,
• nearby organs.

It should not be confused with the primary bone tumor.

Bone metastases form mainly in:

• Spine
• Pelvis
• skull bones,
• Femur
• Humerus.

How do metastases form?

Metastases can occur when tumor cells detach from the primary tumor in which the cancer originated.
The cells can penetrate into blood or lymphatic vessels and thus reach the bone marrow.
The bone marrow matrix secretes cytokines, i.e. proteins that can attract cancer cells.
The tumor cells can remain hidden and inactive in the bone for a longer period of time.
At some time, cells may begin to multiply and form new blood vessels to obtain oxygen and the nutrients they need.
This allows the formation of one or more tumors.

Osteolytic and osteoplastic bone metastases

Bone metastases are usually classified as follows:

1. Osteolytic, when the normal bone is destroyed,
2. Osteoplastic, when the metastases lead to the deposition of new bone tissue.

This distinction is not absolute: many patients have only osteolytic metastases, others only osteoplastic, while others have osteolytic and osteoplastic metastases together.

Forms of cancer that cause bone metastases

Bone is an organ in which metastases often develop.
Almost all types of tumors can spread to the bones, however, some cause metastases more often than others. For example:

• Breast cancer
• Lung cancer
• Prostate cancer
• Kidney
• Thyroid cancer
• Bladder cancer
• Leukaemia – Lyphom
• Malignant melanoma

This list is incomplete and almost all types of tumors can spread to the bones.

Symptoms of bone metastases

In 25% of cases, bone metastases cause no symptoms and the diagnosis is made on the basis of examinations carried out for other reasons.
In the other cases, bone metastases can cause severe acute or chronic pain that worsens as the disease progresses.
At first, it’s often hard to tell what’s causing the symptoms.
One must always remember that not all pain is caused by cancer.
It is important to inform your doctor immediately if you notice any of the following symptoms of bone metastases:

• Bone pain. These are often a first sign of bone metastases. At first, the pain can come and go. They usually intensify at night and get better when moving. Over time, however, the pain no longer passes.
• Fracture. This occurs because the bone metastases weaken the bone and the risk of injury increases. Fractures occur more often:
  • on the spine,
  • on the humerus.
  • on the femur.
• Numbness, paralysis or difficulty urinating. The pressure that bone metastases put on the spinal cord in the lumbar spine can cause these symptoms.
• Loss of appetite, nausea, constipation, frequent urination or fatigue. These symptoms may be caused by high levels of calcium in the blood (hypercalcemia). When metastases develop in the bone, calcium is released into the blood.

Diagnosis of bone metastases

The examinations used to detect bone metastases are:

• Radiography is the first examination that is performed, but it does not show any changes in the bone in the initial stages. In later stages, one can observe bright and extensive areas when a mass has formed, while in osteolytic bone metastasis, a darker spot appears on the X-ray.
• Bone scintigraphy: Today, it is used less to detect bone metastases compared to the past, and it is often difficult to distinguish a tumor from other bone diseases.
• Positron emission tomography (PET): This is a very sensitive procedure to detect bone metastases. It is used to find the growth areas of the tumor active in the bone.
• Nuclear magnetic resonance (NMR).
• Computed tomography (CT).
• Bone biopsy: Part of the bone is taken for laboratory analysis; in this way, it can be determined whether it is a primitive tumor (sarcoma) or a metastasis that does not originate from a bone tumor.
• Blood test to determine tumor markers:
  • alkaline phosphatase,
  • Hydroxyproline
  • Osteocalcin.

Therapy for bone metastases

Orthopaedic surgery
The destruction of metastases reduces the load-bearing capacity of the bone. Therefore, the following may occur:

• fracture of the bone trabeculaeum,
• microfractures,
• complete loss of bone integrity.

Rib fractures and vertebral fractures are common.
The consequences are:

• reduction of body size;
• multiple and severe rib fractures cause kyphoscoliosis;
• Reducing the ability to dilate the lungs.

In most cases, however, the fracture of a long bone (femur, humerus) or the epidural expansion of a tumor in the spine causes most of the body’s disabilities. In these cases, bed rest and hospitalization of the patient are often necessary.
Pathological fractures are not necessarily a manifestation of the incurable disease.
Internal stabilization, followed by radiation therapy, is usually the preferred therapy for a single or small metastasis and allows to restore mobility and relieve pain.
Untreated pathological fractures rarely heal on their own.

External radiation therapy Radiation therapy
uses high-energy radiation, such as X-rays, to kill the tumor cells.
Radiation therapy may be a treatment option:

• to reduce the mass of bone metastases,
• to combat the pain that cannot be relieved with painkillers.

Depending on the case, radiation treatment of the bone can be done with one large dose or several repeated smaller doses.
In most cases, external radiation treatment causes the following side effects:

• redness of the skin,
• Sterility
• joint problems,
• lypmphedema,
• changes in blood cells (anaemia, thrombopenia, leukopenia),
• Hair loss
• Nausea
• Xerostomia
• Fatigue.

Drug therapy
The therapies used for the treatment of bone metastases are:

• Chemotherapy. This therapy uses combinations of different drugs to destroy the tumor cells.
  Since these drugs can affect the whole organism, healthy cells can also be damaged, including:
  – white blood cells,
  – platelets.
  Chemotherapy is carried out in cycles alternating with periods of rest to recover the number of blood cells.
• Hormone or endocrine therapy. This drug treatment is used for tumor types affected by hormones.
  Hormones are chemicals produced by the body glands. In some cancers, hormones can:
  – support the growth of tumor cells and their spread,
  – destroy the tumor cells and prevent their growth. The therapy works by: – raises the hormone level of certain hormones,
  – blocks their production.

  Breast and prostate tumors are examples of primary tumors that are often treated with endocrine therapy.

Clinical use of bisphosphonates
Bisphosphonates against tumor hypercalcemia Hypercalcemia
is one of the most common metabolic complications in cancer and causes many gastrointestinal symptoms and neurological complaints.
Factors that can contribute to the formation of metastases are:

1. local osteolysis of tumor cells,
2. osteolysis by hormones secreted by the tumor; in fact, some hormones stimulate or inhibit osteoclasts (cells responsible for the absorption of calcium in bone),
3. greater absorption of calcium in the kidneys,
4. impairment of renal functions (at the level of glomeruli).

Intravenous bisphosphonates in conjunction with rehydration are now the preferred therapy:

• in hypercalcemia,
• to slow down or stop the resorption of the bone, which stimulates the formation of new metastases.

70-90% of patients achieve normal calcium levels with appropriate relief of symptoms and improvement of quality of life.

Bisphosphonates for bone pain Radiation therapy is the preferred treatment for localized bone pain, but many patients have diffuse, non-movement-related bone pain, while others experience recurrent bone pain
in the previously treated skeletal areas.
Bisphosphonates are a complementary therapy in the treatment of these patients.
Bisphosphonates are drugs that relieve the pain of bone metastases, they can:

• improve the general condition of the bone,
• Prevent fractures.

These drugs are also used for treatment and prevention of:

• Osteoporosis
• other bone diseases, such as Paget’s disease.

Bisphosphonates:

• prevent bone erosion by cells called osteoclasts,
• can indirectly stimulate the osteoblasts that form bone tissue.

The result is:

• the prevention of fractures in bone tumors or bone metastases,
• increased life expectancy of patients.

Zelodronic acid (Zometa) is an example of a bisphosphonate that can be used for the therapy and prevention of bone metastases.
These drugs are administered intravenously every 3-4 weeks.
They are relatively safe, but in rare cases the cause of:

• a complication known as bone necrosis of the upper or lower jaw,
• Kidney damage.

New methods for pain therapy for bone metastases

One of the latest developments in the therapy of bone metastases is the treatment with magnetic resonance-guided focused ultrasound.
This is a pain therapy that eliminates or reduces the tumor mass.
The ultrasound:

• increases the temperature in a circumscribed area of the body,
• causes the death of cells.

The results will be noticeable within three days.
This therapy:

• does not require radiation,
• the side effects (inflammation or burning of the surrounding tissues) are negligible.

Surgical intervention for bone metastases

One operation:

• can help stabilize a bone prone to fracture, which is called an “impending fracture”; the bone in this case is very weak and can break, even at bed rest;
• can repair a fractured bone.

When to operate?

• Bone stabilization surgery. If there is a risk of fracture due to bone metastases, surgeons can stabilize the bone with metal plates, screws and intramedullary nails (orthopedic stabilization). Orthopedic stabilization can relieve pain and improve functionality. Often, radiation therapy is performed after surgery.
• Surgical intervention to inject cement into the bone. Bones that cannot be easily stabilized with metal plates or screws can be stabilized by infiltration with a special bone cement (for example, pelvic and spinal bones). Doctors inject the cement into a broken bone or bone damaged by bone metastases.
  This procedure can relieve pain.
• Operative repair of a fracture. If the bone metastases have caused a bone fracture, surgeons can surgically restore the bone.
  For this, metal plates, screws and nails are used to stabilize the bone.
  A joint replacement, such as a hip prosthesis, can be another option, but is usually performed for:
  • Kidney cancer (clear cell carcinoma)
  • Thyroid cancer.
• Surgical intervention for spinal cord compression. The surgeon must reduce the pressure of metastases on the spinal cord. In this case, the neurosurgeon considers the metastases to be a primitive tumor; the technique consists of:
  • removal of mass,
  • Bone nailing.

Surgical intervention is not indicated if the patient has numerous bone lesions or if they develop rapidly. In this case, the fractures caused by the bone metastases are treated with an orthosis or plaster cast.

Heating and freezing of tumor cells
Procedures to kill cancer cells with heat or cold can help control pain.

Prognosis and life expectancy of patients with bone metastases

In the treatment of metastases in the skeletal apparatus, it is important to know the prognostic factors for healing bone metastases.
There are several factors that predict the survival rate of bone metastases:

1. general health;
2. number of metastases in the vertebral body;
3. metastases on important internal organs;
4. primary area of the tumor;
5. Severity of spinal cord paralysis (neurological symptoms).

About 80% of patients with bone metastases are with metastatic breast cancer.
According to a study published by Yonsei Medical Journal (2013), the average life expectancy of women with metastatic breast cancer who have only bone metastases is about 24-52 months.

Some scientific studies (Hideshi Sugiura, Kenji Yamada et al.) showed the following survival rates for bone metastases caused by lung cancer:

• 59,9 % after 6 months,
• 31,6 % after 1 year,
• 11.3% after 2 years.

The median survival rate is 9.7 months.

Other studies show:

• The average survival rate in patients with stage IV disease is about 6 months.
• The median survival rate in patients with lung cancer and bone metastases is about 5-6 months.
• In approximately 70% of patients with bone metastases, death occurs within one year of mass formation.
• Although the prognosis for patients with lung cancer and bone metastases is poor, 7 patients out of 118 (6%) survived for at least 2 years. Two patients with isolated metastasis who survived longer with metastatic bone resection and chemotherapy have been reported.
• It also became known the case of a patient with an isolated bone metastasis, who survived even longer with aggressive treatment.

• Bone pain
• Bone tumour
• Bone pain