Metastatic Bone Disease

Metastatic bone disease is the most common malignancy affecting bone, far exceeding primary bone tumors. The BPLTK primaries (Breast, Prostate, Lung, Thyroid, Kidney) account for most cases, with metastases preferentially affecting the axial skeleton following red marrow distribution. The Mirels scoring system predicts pathological fracture risk using 4 parameters (Site, Pain, Lesion type, Size)—scores greater than 8 indicate prophylactic fixation due to greater than 33% fracture risk. Blastic lesions suggest prostate (most common), while lytic lesions (kidney, thyroid, lung) are structurally weaker. Kidney and thyroid metastases are highly vascular and require preoperative embolization. Management is palliative with durable constructs allowing immediate weight-bearing.

Metastatic bone disease is the most common malignancy affecting bone, far exceeding primary bone tumors in frequency.

Epidemiology

• Incidence: 25-30x more common than primary bone tumors
• Prevalence: Found at autopsy in 70-85% of patients with breast/prostate cancer
• Age: Typically middle-aged to elderly (reflecting primary cancer demographics)
• Impact: 350,000-400,000 people living with bone metastases in USA

Common Primary Tumors (BPLTK)

1. Breast: Most common source overall and in women
2. Prostate: Most common source in men
3. Lung: Third most common; poor prognosis
4. Thyroid: Differentiated carcinoma has better prognosis
5. Kidney: Renal cell carcinoma; very vascular

Less Common Primaries

• Gastrointestinal (colon, stomach)
• Bladder
• Melanoma
• Unknown primary (10-15% of cases)

Distribution (Red Marrow Distribution)

• Spine: 70% - most common site (thoracic greater than lumbar greater than cervical)
• Pelvis: 40%
• Proximal Femur: 25%
• Ribs: 25%
• Skull: 15%
• Proximal Humerus: 15%

Mechanisms of Bone Metastasis

Metastatic Cascade:

1. Primary Tumor Growth: Cancer cells proliferate in organ of origin
2. Local Invasion: Tumor penetrates basement membrane
3. Intravasation: Entry into bloodstream or lymphatics
4. Circulation: Survival in circulation (most cells die)
5. Extravasation: Exit from vessels at distant site
6. Colonization: Establish growth in bone microenvironment

Why Bone?

• Hematogenous Spread: Most common route to bone
• Batson's Venous Plexus: Valveless vertebral venous system allows retrograde flow
  • Explains predilection for spine and axial skeleton
  • Low-pressure system facilitates tumor cell lodging
• Red Marrow Distribution: Sites with active hematopoiesis
  • Rich blood supply
  • Growth factors present
  • Supportive microenvironment

The Vicious Cycle

Seed and Soil Hypothesis (Paget 1889): Cancer cells (seed) preferentially grow in bone microenvironment (soil)

The Cycle:

1. Tumor cells arrive in bone marrow
2. Tumor cells secrete factors (PTHrP, IL-6, TNF) → stimulate osteoclasts
3. Osteoclasts resorb bone → release growth factors (TGF-β, IGF, BMPs)
4. Growth factors stimulate tumor → more factor secretion
5. Cycle perpetuates → progressive bone destruction

Lytic vs Blastic Metastases

Lytic Lesions (Bone Destruction):

• Kidney, thyroid, lung
• Osteoclast activation dominant
• Structurally weak bone
• High fracture risk
• Mechanisms: PTHrP, IL-1, IL-6, TNF-α

Blastic Lesions (Bone Formation):

• Prostate (most), treated breast, small cell lung
• Osteoblast activation dominant
• Dense but disorganized bone (structurally weak)
• Lower fracture risk
• Mechanisms: Endothelin-1, BMPs, Wnt signaling

Mixed Lesions:

• Breast (untreated), GI cancers
• Both processes active

Role of RANK/RANKL Pathway

• RANK: Receptor on osteoclast precursors
• RANKL: Ligand secreted by osteoblasts and tumor cells
• RANKL binding to RANK: Osteoclast activation and differentiation
• OPG (osteoprotegerin): Decoy receptor, inhibits RANKL
• Therapeutic target: Denosumab (RANKL inhibitor)

History

• Known Cancer: 85% have known primary at presentation
• Unknown Primary: 15% bone metastasis is first presentation of cancer
• Pain: Most common symptom
  • Night pain (classic)
  • Activity-related (mechanical instability)
  • Rest pain (tumor growth)
• Pathological Fracture: May be presenting feature
• Neurological: Spinal cord compression (weakness, sensory changes, bladder/bowel)
• Constitutional: Weight loss, fatigue, anorexia

Physical Examination

Examination Approach

1. Local Assessment

   • Point tenderness over lesion
   • Palpable mass (large lesions)
   • Surrounding soft tissue swelling

2. Fracture Assessment

   • Deformity, shortening
   • Inability to weight-bear
   • Crepitus (do not elicit if suspected)

3. Neurological Assessment (Spine)

   • Motor: Power in myotomes
   • Sensory: Dermatomal distribution
   • Reflexes: Hyperreflexia (UMN) or hyporeflexia
   • Bladder/bowel function
   • Rectal tone, perianal sensation

4. Systemic Assessment

   • Breast examination
   • Prostate examination (DRE)
   • Thyroid palpation
   • Lymphadenopathy
   • Abdominal masses
   • General condition, performance status

Red Flags for Cord Compression

• New back pain in cancer patient
• Bilateral leg symptoms
• Bladder/bowel dysfunction
• Progressive weakness
• Sensory level

Imaging

Plain Radiographs:

• First-line investigation
• Lytic (dark, destructive) vs Blastic (white, sclerotic) vs Mixed
• Need 30-50% cortical destruction to be visible
• Assess fracture risk, deformity

CT Scan:

• Better cortical assessment than X-ray
• Quantify bone destruction
• CT chest/abdomen/pelvis for staging
• CT-guided biopsy planning

MRI:

• Most sensitive for marrow involvement
• Essential for spinal metastases
• Assesses soft tissue extension
• Whole spine MRI if cord compression suspected

Bone Scintigraphy (Bone Scan):

• Whole-body screening
• Highly sensitive but low specificity
• May miss pure lytic lesions (kidney, myeloma)
• Superscan = widespread metastases

PET-CT:

• Increasingly used for staging
• Assesses metabolic activity
• Helps identify unknown primary
• Monitors treatment response

Laboratory Investigations

• Full Blood Count: Anaemia, pancytopenia (marrow infiltration)
• Biochemistry: Calcium (hypercalcemia), ALP (elevated), LDH
• Tumor Markers: PSA (prostate), CEA (GI, breast), AFP (germ cell), thyroglobulin
• Serum/Urine Protein Electrophoresis: Exclude myeloma
• Iron Studies: Chronic disease pattern

Biopsy

Indications:

• Unknown primary tumor
• Solitary lesion (could be primary bone tumor)
• Atypical presentation
• Clinical doubt about diagnosis

Technique:

• Image-guided core needle biopsy (preferred)
• Align biopsy tract with potential surgical approach
• Tissue for histology, immunohistochemistry, molecular studies

Differential Diagnosis of a Destructive Bone Lesion

Unknown Primary

• 10-15% of bone metastases have no known primary
• Workup: CT CAP, PET, tumor markers, serum/urine electrophoresis
• Biopsy essential for diagnosis and treatment planning
• Immunohistochemistry directs investigation

Solitary Metastasis

• May represent oligometastatic disease
• Consider aggressive local treatment
• Wide resection + adjuvant therapy in selected cases
• Better prognosis than polymetastatic disease

Renal Cell Carcinoma (Special Case)

• Very vascular - MUST embolize
• May be radiosensitive (modern targeted therapy)
• Solitary metastasis: Consider nephrectomy + metastasectomy
• Targeted therapy (TKIs, immunotherapy) have improved outcomes

Pathological Fracture vs Impending Fracture

• Actual fracture: Fix urgently, control pain
• Impending fracture: Elective prophylactic fixation
• Better outcomes with prophylactic surgery than fracture fixation

Bone is the third most common site of metastasis after lung and liver. Breast, prostate, lung, thyroid and kidney account for the great majority of skeletal metastases, and bone metastases drive a heavy burden of skeletal-related events (SREs) regardless of health system.

Global Epidemiology

Major Guidance, Side by Side

Registry and Practice Variation

• No dedicated international "bone-metastasis implant" registry exists; outcomes are drawn from oncology trial datasets and institutional series rather than arthroplasty-style joint registries.
• Practice variation: single-fraction radiotherapy uptake varies widely between countries despite equivalent efficacy, reflecting reimbursement and capacity rather than evidence. Preoperative embolization for renal/thyroid metastases is standard in tertiary centres but its measured benefit is greatest for large lesions and open reconstructions, and is less consistent for intramedullary nailing and non-renal primaries (Pazionis 2014, Robial 2012).
• Resource-limited settings: where interventional radiology, endoprostheses or radiotherapy are scarce, management shifts toward cemented internal fixation and single-fraction radiotherapy; late presentation with established fracture or cord compression is more common, worsening functional outcome.