Bone Metastases

Bone metastases are the most common malignant bone lesions in adults — far outnumbering primary bone sarcomas. The skeleton is the third most common site of metastasis after the lung and liver, and bone is frequently the first site of distant spread in carcinomas of the breast and prostate. These notes cover the classic primary sources, lytic-versus-sclerotic patterns, Mirels scoring for impending fracture, the imaging workhorses (bone scan vs PET-CT), and the orthopaedic and oncological management algorithm.

Definition & basic concepts

A bone metastasis (secondary bone tumour) is the seeding of malignant cells from a distant primary carcinoma into bone, where they proliferate and disrupt normal bone remodelling. Metastasis to bone occurs chiefly via haematogenous spread, with a strong predilection for the red-marrow-rich axial skeleton — vertebrae, pelvis, ribs, skull, and proximal femur/humerus. Distal-to-elbow and distal-to-knee (acral) metastases are rare; when a lesion is found in the hand or foot, lung carcinoma is the classic primary (acrometastasis).

High-yield: The most common malignant tumour of bone overall is metastasis, NOT multiple myeloma. The most common primary malignant bone tumour is osteosarcoma; the most common primary marrow malignancy is myeloma.

The "famous five" primaries (in order)

The carcinomas that most frequently metastasise to bone are remembered by the mnemonic "BLT with a Kosher Pickle" → Breast, Lung, Thyroid, Kidney, Prostate.

• In women: breast carcinoma is the leading source.
• In men: prostate carcinoma is the leading source.
• Overall, breast and prostate together account for the majority of skeletal metastases because of their high incidence and long survival.

Pathophysiology — the "vicious cycle"

Bone is a metabolically active organ where osteoblastic bone formation and osteoclastic resorption are normally coupled. Tumour cells subvert this balance.

Osteolytic (lytic) mechanism: Tumour cells secrete parathyroid hormone–related peptide (PTHrP), interleukins (IL-6, IL-11) and prostaglandins, which upregulate RANKL on osteoblasts/stromal cells. RANKL binds RANK on osteoclast precursors → osteoclast activation → bone resorption. Resorption liberates growth factors stored in the matrix (TGF-β, IGF, calcium) that in turn stimulate further tumour growth — the self-perpetuating "vicious cycle" of Mundy. This drives hypercalcaemia of malignancy.

Osteoblastic (sclerotic) mechanism: Tumour cells (classically prostate) secrete factors such as endothelin-1, Wnt ligands, BMPs and PDGF that drive osteoblast proliferation and disorganised woven-bone deposition. The new bone is structurally weak despite being radiodense.

High-yield: RANKL is the central cytokine of osteolysis — this is why denosumab (anti-RANKL monoclonal antibody) and bisphosphonates (osteoclast inhibitors) are pillars of therapy.

Lytic vs sclerotic vs mixed — pattern recognition

This table is among the most repeatedly tested facts in the topic.

Pattern	Classic primaries	Key feature
Osteolytic	Lung, Kidney (renal cell), Thyroid, GI tract, Multiple myeloma, Melanoma	Bone destruction, "punched-out" / moth-eaten; risk of pathological fracture & hypercalcaemia
Osteoblastic (sclerotic)	Prostate, carcinoid, medulloblastoma, small-cell lung, Hodgkin lymphoma	Dense, radio-opaque; raised ALP; low fracture risk
Mixed	Breast, GI adenocarcinoma, ovarian	Combination of lysis and sclerosis

Mnemonics worth memorising:

• Lytic primaries → "Lead Kettle" = Lung, Kidney, Thyroid, GI, Multiple myeloma (think "LKTM").
• Sclerotic / blastic → "5 B's" = Breast (mixed), Bladder (urothelial), Bowel (mucinous), Bronchus (small-cell/carcinoid), and Prostate (the most blastic of all).

High-yield: Renal cell carcinoma and thyroid carcinoma produce characteristically expansile, "blow-out", highly vascular lytic lesions — pre-operative embolisation is often performed to reduce catastrophic intra-operative haemorrhage during fixation.

High-yield: Multiple myeloma is typically "cold" (negative) on a technetium bone scan because it is purely lytic with little reactive osteoblastic activity — a skeletal survey or whole-body MRI/PET is preferred. This is a perennial exam discriminator.

Clinical features

• Bone pain — the commonest symptom; classically progressive, worse at night and at rest, poorly relieved by position. New persistent bone pain in a patient with known carcinoma is metastasis until proven otherwise.
• Pathological fracture — fracture through abnormal bone after trivial or no trauma; femur (especially subtrochanteric) and vertebrae are common sites.
• Spinal cord / cauda equina compression — an oncological emergency presenting with back pain, limb weakness, sensory level, and sphincter disturbance.
• Hypercalcaemia — "stones, bones, groans, psychic moans": polyuria, constipation, confusion, arrhythmia.
• Marrow infiltration → anaemia, leukoerythroblastic blood film, cytopenias.
• Presentation as the first sign of an occult cancer — particularly lung and kidney, where a destructive bone lesion may be the index finding.

Investigations & investigation of choice

A logical work-up answers two questions: Where is the disease? and What is the primary?

Stepwise diagnostic approach:

1. Plain radiograph (X-ray) of the symptomatic site → first and cheapest; detects lytic/sclerotic pattern, cortical involvement, fracture risk. Limitation: ~30–50% of trabecular bone must be lost before lysis is radiographically visible.
2. Technetium-99m MDP bone scan (scintigraphy) → the traditional whole-body screening test; highly sensitive for osteoblastic activity, detects lesions weeks-to-months earlier than X-ray. Pitfalls: false-negative in purely lytic disease (myeloma, aggressive RCC) and false-positive in degenerative/inflammatory/healing bone.
3. MRI → most sensitive for marrow infiltration and the investigation of choice for suspected cord compression (whole-spine MRI).
4. CT → best for assessing cortical destruction and guiding biopsy; CT chest/abdomen/pelvis helps locate an unknown primary.
5. PET-CT (18F-FDG) → superior for lytic and marrow-based disease, simultaneous detection of primary and soft-tissue/visceral metastases; increasingly the single-test staging modality.
6. Biopsy → mandatory when there is a solitary bone lesion of unknown origin or no known primary, to confirm metastasis vs primary sarcoma vs myeloma and to obtain receptor status (ER/PR/HER2, etc.).
7. Labs: raised ALP (osteoblastic activity), serum calcium, PSA (prostate), thyroglobulin, serum/urine electrophoresis (to exclude myeloma), FBC, renal function.

Modality	Best for	Weakness
Plain X-ray	Initial assessment, fracture, pattern	Insensitive early (needs 30–50% bone loss)
Tc-99m bone scan	Whole-body osteoblastic screen	Misses lytic/myeloma; false +ve in arthritis
MRI	Marrow & cord compression	Limited body coverage, costlier
FDG PET-CT	Lytic disease, primary + visceral staging	Cost; sclerotic prostate mets may be FDG-low

High-yield: PET-CT vs bone scan — Bone scan relies on osteoblastic reaction, so it excels in prostate (blastic) disease and misses lytic disease. PET-CT detects the tumour cells themselves, so it is superior for lytic and marrow metastases but can underperform in densely sclerotic, low-metabolic prostate lesions (where PSMA-PET now leads).

High-yield: Single, solitary bone lesion in a patient WITHOUT a known primary → biopsy before any fixation. Never internally fix a presumed metastasis that could actually be a primary sarcoma — inappropriate surgery contaminates compartments and worsens limb-salvage prognosis. This is a classic exam trap.

Mirels scoring — impending pathological fracture

The Mirels scoring system quantifies the risk of pathological fracture in a long bone with a metastatic deposit and guides prophylactic fixation. Four variables, each scored 1–3, summed (range 4–12).

Variable	1 point	2 points	3 points
Site	Upper limb	Lower limb	Peritrochanteric
Pain	Mild	Moderate	Functional (mechanical)
Lesion type	Blastic	Mixed	Lytic
Size (cortex)	< 1/3	1/3 – 2/3	> 2/3

Interpretation:

• Score ≤ 7 → low risk (~5%): manage conservatively with radiotherapy + observation.
• Score = 8 → borderline (~15%): clinical judgement.
• Score ≥ 9 → high risk (>33%): prophylactic internal fixation BEFORE irradiation.

High-yield: A score of 9 or more mandates prophylactic fixation. The single most weighted clinical factor is a peritrochanteric lytic lesion with functional (mechanical) pain involving > 2/3 of the cortex = maximal 12. Fix first, then radiate — fixing a fractured bone is harder and outcomes are worse than prophylactic fixation.

A simpler bedside rule: a lytic lesion > 2.5 cm, > 50% cortical destruction, or avulsion of the lesser trochanter also signals high fracture risk and need for fixation.

Management

Treatment of bone metastasis is almost always palliative — aimed at pain relief, preserving function/mobility, preventing or treating fractures and cord compression, and maintaining quality of life. It is multidisciplinary (oncology, orthopaedics, radiation oncology, palliative care).

Stepwise treatment of an impending/actual fracture

Assess (Mirels) → Biopsy if primary unknown → Prophylactic fixation if Mirels ≥ 9 / actual fracture → Post-operative radiotherapy to the whole implant → Systemic therapy (bisphosphonate/denosumab + treat primary) → Palliative analgesia & rehab.

1. Systemic bone-targeted agents

• Bisphosphonates — zoledronic acid (drug of choice; IV, most potent) and pamidronate. They inhibit osteoclast-mediated resorption, reduce skeletal-related events (SREs) — fracture, cord compression, need for surgery/radiation — and treat hypercalcaemia.
  • Adverse effects to remember: osteonecrosis of the jaw (ONJ) — ensure dental clearance before starting; renal impairment; acute-phase flu-like reaction; hypocalcaemia (supplement calcium + vitamin D); atypical subtrochanteric femoral fractures with prolonged use.
• Denosumab — RANKL inhibitor; subcutaneous, not renally cleared so preferred in renal impairment; also causes ONJ and hypocalcaemia. Shown to delay SREs at least as effectively as zoledronic acid.

High-yield: Zoledronic acid is the drug of choice for hypercalcaemia of malignancy (after IV saline rehydration) and for reducing SREs. Denosumab is preferred when renal function is poor. Both require calcium + vitamin D supplementation and dental assessment to prevent ONJ.

2. Radiotherapy

• External beam radiotherapy (EBRT) is the cornerstone of pain palliation — effective in ~70–80%. A single 8 Gy fraction is as effective as multifraction regimens for uncomplicated painful bone metastasis (though retreatment rates are higher).
• Indications: localised bone pain, post-operative consolidation over fixation, spinal cord compression, impending fracture not meeting fixation criteria.
• Radio-pharmaceuticals: Strontium-89, Samarium-153 for diffuse blastic (prostate) pain; Radium-223 (alpha-emitter) improves survival in castration-resistant prostate cancer with symptomatic bone mets.

3. Surgery (orthopaedic intervention)

Goals: durable fixation allowing immediate weight-bearing, single anaesthetic, construct that outlives the patient.

• Long-bone (femur/humerus): prophylactic intramedullary nailing for impending fracture — the IM nail protects the entire bone, not just the lesion. Cement augmentation (PMMA) increases stability.
• Periarticular / extensive destruction: endoprosthetic replacement (e.g. proximal femoral or hip megaprosthesis), often cemented.
• Spine: decompression + instrumented stabilisation for cord compression with mechanical instability; vertebroplasty/kyphoplasty for painful vertebral collapse without neurology.
• Pre-operative embolisation for hypervascular renal and thyroid metastases.

High-yield: Metastatic spinal cord compression (MSCC) — start high-dose dexamethasone immediately, urgent whole-spine MRI, and surgical decompression + stabilisation followed by radiotherapy is superior to radiotherapy alone (Patchell trial) in suitable surgical candidates. Treat within 24–48 h to preserve neurology.

4. Treat the primary & supportive care

Hormone therapy (prostate, breast ER+), chemotherapy, targeted/immunotherapy, radioactive iodine for thyroid, plus WHO analgesic ladder, treatment of hypercalcaemia (IV saline + zoledronic acid ± calcitonin for rapid drop), and physiotherapy.

Complications

• Pathological fracture (notably subtrochanteric femur).
• Hypercalcaemia of malignancy — most common metabolic emergency; medical emergency if symptomatic.
• Metastatic spinal cord / cauda equina compression — neurological emergency.
• Bone-marrow suppression — anaemia, leukoerythroblastic picture, pancytopenia.
• Intractable pain and loss of mobility/independence.
• Treatment-related: ONJ, atypical fractures, renal toxicity (bisphosphonates); radiation-induced myelosuppression.

Key differentials

When facing a destructive bone lesion, distinguish metastasis from these mimics:

Differential	Discriminating clue
Multiple myeloma	Older adult, bone-scan negative lytic "punched-out" lesions, M-band on electrophoresis, raised ESR, normal ALP, renal failure
Primary bone sarcoma (osteosarcoma, chondrosarcoma)	Younger patient, solitary, aggressive periosteal reaction; biopsy mandatory before surgery
Lymphoma of bone	Permeative lytic lesion, relatively well patient ("too much bone destruction for how well the patient looks")
Paget's disease	Older patient, bone expansion + cortical thickening, very high ALP with normal calcium, "candle-flame"/coarse trabeculae
Brown tumour (hyperparathyroidism)	Raised PTH & calcium, subperiosteal resorption
Bone infarct / osteomyelitis	Clinical context, raised inflammatory markers

High-yield: Myeloma vs metastasis — both give multiple lytic lesions, but myeloma is bone-scan cold, ALP normal/low, with paraproteinaemia, whereas osteoblastic metastases are bone-scan hot with raised ALP. A solitary lytic lesion in a patient over 40 with a renal or lung primary, or none found, demands a biopsy.

Prognosis (quick orientation)

Bone-only metastatic disease generally carries a better prognosis than visceral metastasis. Median survival varies widely by primary: prostate and breast (months to years, hormone-responsive) fare better than lung (often weeks–months). Solitary, resectable renal or thyroid metastasis may warrant aggressive metastasectomy with prolonged survival.

Recently asked / exam angle

• Most common malignant tumour of bone = metastasis (not myeloma) — repeatedly tested one-liner.
• Mirels score ≥ 9 → prophylactic internal fixation (commonly given a clinical vignette: peritrochanteric lytic lesion, mechanical pain, >2/3 cortex → calculate the score).
• Which primary is osteoblastic? → Prostate. Which are lytic? → Lung, kidney, thyroid, GI, myeloma.
• Bone scan negative tumour → Multiple myeloma (and very lytic RCC).
• Hypervascular metastasis needing pre-op embolisation → Renal cell carcinoma (and thyroid).
• Acrometastasis (hand/foot) → bronchogenic (lung) carcinoma.
• Drug of choice for hypercalcaemia of malignancy → IV zoledronic acid after saline rehydration.
• Bone-targeted agent of choice in renal impairment → denosumab.
• Single-fraction 8 Gy EBRT for uncomplicated painful bone metastasis.
• Radium-223 improves survival in castration-resistant prostate cancer bone metastases (alpha-emitter).
• MSCC management: dexamethasone + urgent MRI + surgery then radiotherapy (Patchell).
• Most common site of skeletal metastasis = vertebral column (thoracic/lumbar spine); spread often via Batson's vertebral venous plexus (valveless), explaining prostate → lumbar spine spread.

Rapid revision

1. Metastasis is the most common malignant bone lesion; primaries = Breast, Lung, Thyroid, Kidney, Prostate.
2. Prostate = osteoblastic; breast = mixed; lung/kidney/thyroid/GI/myeloma = lytic.
3. Multiple myeloma is bone-scan negative — use skeletal survey/PET/MRI.
4. Renal & thyroid mets are hypervascular → embolise before fixation.
5. Acrometastasis = lung carcinoma until proven otherwise.
6. Mirels ≥ 9 (max 12) → prophylactic IM nailing; fix first, radiate after.
7. Maximal Mirels factors: peritrochanteric, lytic, functional pain, >2/3 cortex.
8. Solitary lesion + unknown primary → biopsy before any internal fixation.
9. Bone scan = osteoblastic activity (good for prostate); PET-CT better for lytic/marrow disease.
10. Zoledronic acid = DOC for SRE reduction & malignant hypercalcaemia; denosumab if renal impairment; both risk ONJ (dental clearance first).
11. MSCC = emergency → dexamethasone + MRI whole spine + decompressive surgery then RT.
12. Spread to spine via Batson's valveless venous plexus; single 8 Gy fraction palliates bone pain effectively.