Malignant bone disease (osteosarcoma)

Malignant Bone Disease & Osteosarcoma: Overview

Understanding the fundamental structure of bone tissue is crucial for comprehending the mechanisms underlying malignant bone diseases, including primary tumors like osteosarcoma and metastatic disease [1].

Bone is a specialized connective tissue comprising cells and an extracellular matrix [1]. The extracellular matrix consists of:

• Organic component (Osteoid): Primarily Type I collagen (~90-95%), providing tensile strength, along with non-collagenous proteins (e.g., osteocalcin, osteonectin) involved in mineralization and regulation [1].
• Inorganic component: Mainly calcium phosphate crystals (hydroxyapatite), providing hardness and rigidity [1].

Bone cells include osteoblasts (bone-forming), osteocytes (mature cells sensing mechanical load), and osteoclasts (bone-resorbing) [1].

 

Pathophysiology of Bone Involvement by Tumors

Normal bone undergoes continuous remodeling, a balance between resorption by osteoclasts and formation by osteoblasts [1, 2]. Malignant processes disrupt this balance [2, 3].

• Direct Invasion/Destruction: Primary bone tumors (like osteosarcoma) or metastatic tumors directly destroy bone tissue [3].
• Stimulation of Osteoclasts: Many tumors (especially metastases from breast, lung, kidney cancer; multiple myeloma; lymphomas) secrete factors like cytokines (e.g., RANKL, interleukins) or growth factors that stimulate osteoclast activity [2, 3]. This leads to excessive local bone resorption (osteolysis), weakening the bone.

This accelerated bone resorption is a key mechanism leading to complications like pathological fractures (fractures occurring with minimal or no trauma due to weakened bone) and pain [2, 3]. Vertebral bodies are common sites for metastases and myeloma, and pathological compression fractures here can cause spinal cord or nerve root compression, representing neurological emergencies [3].

Multiple myeloma, a cancer of plasma cells, is a frequent cause of osteolytic lesions and pathological fractures, sometimes requiring urgent surgical stabilization [3].

Hypercalcemia of Malignancy

Hypercalcemia (high blood calcium) is a common metabolic complication of malignancy [2, 3]. There are two main mechanisms:

1. Osteolytic Hypercalcemia: Caused by extensive bone destruction from metastases or myeloma releasing calcium into the blood. Cytokines released by tumor cells stimulate local osteoclast activity [2, 3].
2. Humoral Hypercalcemia of Malignancy (HHM): Certain solid tumors (e.g., squamous cell carcinomas of lung, head/neck; renal, bladder, ovarian cancers; less commonly osteosarcoma itself, though some sarcomas can produce it) secrete Parathyroid Hormone-related Peptide (PTHrP) [2, 3]. PTHrP mimics the action of PTH on bone (increasing resorption) and kidney (increasing calcium reabsorption), leading to hypercalcemia [2]. Importantly, PTHrP is structurally different from PTH and is not detected by standard PTH immunoassays; thus, in HHM, PTH levels are appropriately suppressed by the high calcium [2]. Other humoral factors like cytokines can also contribute [2].