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Secondary bone cancer

Pathology and promising therapeutics

Introduction: what is secondary bone cancer?


Secondary bone cancer occurs when cancer cells spread to the bones from a tumour that started somewhere else in the body.

 

The site where the tumour first develops is called primary cancer. Cancer cells can break away from the primary cancer, travel through the bloodstream or lymphatic system, and establish secondary cancers, known as metastasis.

 

Bones are among the most common sites to which cancer can spread. Most type of cancer has the potential to metastasise to the bones, with the most frequent occurrences seen in prostate, breast, lung, thyroid, kidney, and myeloma cancers. Throughout the literature, secondary cancer in the bones is referred to as bone secondaries or bone metastases.

 

The most common areas of secondary bone cancer are the spine, ribs, pelvis, humerus (upper bone of the arm), femur (upper bone of the leg) and skull.

 

There are two main types of bone cancer referred to as osteolytic and osteoblastic metastases. In osteolytic metastases, cancer cells break down the bone, leading to significant weakening. This type of metastasis is more common than osteoblastic metastases and often occurs when breast cancer spreads to the bone.

 

In osteoblastic metastases, cancer cells invade the bone and stimulate excessive bone cell formation. This process results in the bone becoming very dense (sclerotic). Osteoblastic metastases frequently occur when prostate cancer spreads to the bone. Although new bone forms, it grows abnormally, which weakens the overall bone structure.

 

Hormone therapy


Like primary bone cancer, treatment for secondary bone cancer includes surgical excision, chemotherapy, and radiation therapy. Treatment for secondary bone cancer aims to control the cancer growth and symptoms. Treatment depends on several factors, including the type of primary cancer, previous treatment, the number of bones affected by cancer, whether cancer has spread to other body parts, overall health, and symptoms.

 

Breast and prostate cancers rely on hormones for their growth. Reducing hormone levels in the body can be effective in managing the proliferation of secondary cancer. Hormone therapy, also known as endocrine therapy, uses synthetic hormones to inhibit the impact of the body’s innate hormones. Typical side effects include hot flashes, mood fluctuations, changes in weight, and sweating.

 

Bisphosphonates


Bone is a dynamic tissue with a continuous process of bone formation and resorption. Osteoclasts are cells responsible for breaking down bone tissue. In secondary bone cancer, cancer cells often produce substances that stimulate the activity of osteoclasts. This leads to elevated levels of calcium in the blood (hypercalcemia), resulting in feelings of nausea and excessive thirst.

 

Treating secondary bone cancer involves strengthening bones, alleviating bone pain and managing hypercalcaemia). One option for bone-strengthening is bisphosphonates.

 

Bisphosphonates can be administered orally or intravenously. They have been in clinical practice for over 50 years and are used to treat metabolic bone diseases, osteoporosis, osteolytic metastases, and hypercalcaemia. These compounds selectively target osteoclasts to inhibit their function.

 

Bisphosphonates can be classified into two pharmacologic categories based on their mechanism of action. Nitrogen-containing bisphosphonates, the most potent class, function by suppressing the activity of farnesyl pyrophosphate synthase, a key factor in facilitating the binding of osteoclasts to bone. Consequently, this interference causes the detachment of osteoclasts from the bone surface, effectively impeding the process of bone resorption. Examples of these bisphosphonates include alendronate and zoledronate.

 

Bisphosphonates without nitrogen in their chemical structure are metabolised intracellularly to form an analogue of adenosine triphosphate (ATP), known as 5'-triphosphate pyrophosphate (ApppI). ApppI is a non-functional molecule that disrupts cellular energy metabolism, leading to osteoclast cell death (apoptosis) and, consequently, reduced bone resorption. Examples of these bisphosphonates include etidronate and clodronate.

 

Non-nitrogen-containing bisphosphonates can inhibit bone mineralisation and cause osteomalacia, a condition characterised by bones becoming soft and weak. Due to these considerations, they are not widely utilised.


Denosumab


Denosumab is another option for bone strengthening. It is administered as an injection under the skin (subcutaneously). Denosumab is a human monoclonal antibody that inhibits RANKL to prevent osteoclast-mediated bone resorption. Denosumab-mediated RANKL inhibition hinders osteoclast maturation, function, and survival in contrast to bisphosphonates, which bind to bone minerals and are absorbed by mature osteoclasts.

 

In some studies, Denosumab demonstrated equal or superior efficacy compared to bisphosphonates in preventing skeletal-related events (SREs) associated with bone metastasis. Denosumab’s mechanism of action provides a targeted approach that may offer benefits for specific populations, such as patients with renal impairment.

 

Bisphosphonates are excreted from the human body by the kidneys. A study by Robinson and colleagues demonstrated that bisphosphonate users had a 14% higher risk of chronic kidney disease (CKD) stage progression (including dialysis and transplant) than non-users. On the other hand, denosumab is independent of renal function and less likely to promote deteriorations in kidney function.


Take-home message


Secondary bone cancer, resulting from the spread of cancer cells to the bones, poses challenges across various cancers. Two main types, osteolytic and osteoblastic metastases, impact bone structure differently. Hormone therapy, bisphosphonates, and Denosumab have shown promising results and offer effective management of secondary bone cancers. Ultimately, the decision between treatments should be made in consultation with a healthcare professional who can evaluate the specific clinical situation and individual patient factors. The choice should be tailored to meet the patient’s needs and treatment goals.



Written by Favour Felix-Ilemhenbhio


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