Metastatic Bone Disease

Metastatic bone disease is the most common malignancy affecting bone, far exceeding primary bone tumours: about 25-30 times more common. It is found at autopsy in 70-85% of patients with breast or prostate cancer, and 350,000-400,000 people are living with bone metastases in the USA. Patients are typically middle-aged to elderly, because the age profile is that of the cancers that seed them.

The primaries. Five carcinomas account for most cases: breast, prostate, lung, thyroid and kidney. Breast is the most common source overall and in women, prostate the most common in men, and lung the third; renal cell carcinoma is very vascular. Less common sources are the gastrointestinal tract (colon and stomach), bladder and melanoma, and in 10-15% of cases no primary is known when the bone lesion is found.

View larger

Where they go. Deposits follow the distribution of red marrow, which is why the axial skeleton dominates:

• Spine - 70%, the most common site; thoracic more than lumbar more than cervical
• Pelvis - 40%
• Proximal femur - 25%
• Ribs - 25%
• Skull - 15%
• Proximal humerus - 15%

The metastatic cascade. A cell that ends up in bone has survived six steps:

1. Primary tumour growth - proliferation in the organ of origin
2. Local invasion - the tumour penetrates the basement membrane
3. Intravasation - entry into the bloodstream or lymphatics
4. Circulation - survival in the circulation, where most cells die
5. Extravasation - exit from the vessels at the distant site
6. Colonisation - growth established in the bone microenvironment

Why bone. Spread is haematogenous in most cases. Batson's venous plexus, the valveless vertebral venous system, allows retrograde flow, and its low pressure lets tumour cells lodge; that explains the predilection for the spine and axial skeleton. Red marrow adds a rich blood supply, growth factors and a supportive microenvironment, which is Paget's seed and soil hypothesis (1889): the cancer cell is the seed, the bone microenvironment the soil in which it preferentially grows.

The vicious cycle. Once tumour cells arrive in the marrow they secrete PTHrP, IL-6 and TNF, which stimulate osteoclasts. Osteoclasts resorb bone and release the growth factors stored in it, TGF-β, IGF and BMPs, and those stimulate the tumour to secrete more. The cycle perpetuates itself and the bone is progressively destroyed.

Lytic, blastic and mixed. Which side of the cycle dominates decides what the radiograph shows and how strong the bone is.

• Lytic (kidney, thyroid, lung): osteoclast activation dominates, driven by PTHrP, IL-1, IL-6 and TNF-α. The bone is structurally weak and the fracture risk high.
• Blastic (prostate above all, treated breast, small cell lung): osteoblast activation dominates, driven by endothelin-1, BMPs and Wnt signalling. The bone formed is dense but disorganised, so it is still structurally weak, though the fracture risk is lower than in lytic disease.
• Mixed (untreated breast, gastrointestinal cancers): both processes are active.

RANK and RANKL. RANK is the receptor on osteoclast precursors; RANKL is its ligand, secreted by osteoblasts and by tumour cells. RANKL binding to RANK drives osteoclast differentiation and activation, and osteoprotegerin (OPG) is the decoy receptor that inhibits it. The pathway is the target of denosumab, a RANKL inhibitor.

History. Most patients, about 85%, already have a cancer diagnosis; in 10-15% the bone lesion is the first presentation of the cancer. Pain is the most common symptom, and its pattern suggests its cause: night pain is the classic, activity-related pain suggests mechanical instability, and rest pain suggests tumour growth. A pathological fracture may be the presenting feature. Ask about weakness, sensory change and bladder or bowel symptoms, which suggest cord compression, and about weight loss, fatigue and anorexia.

Examination. Four things to cover:

• Local - point tenderness over the lesion, a palpable mass with large lesions, surrounding soft-tissue swelling
• Fracture - deformity, shortening, inability to weight-bear; crepitus, which you do not elicit if a fracture is suspected
• Neurological, for spinal disease - power by myotome, sensation by dermatome, reflexes (hyperreflexia with an upper motor neurone lesion, or hyporeflexia), bladder and bowel function, rectal tone and perianal sensation
• Systemic, looking for the primary - breast, prostate (digital rectal examination), thyroid, lymph nodes, abdominal masses, and general condition and performance status

Red flags for cord compression. Any of these in a patient with cancer:

• New back pain
• Bilateral leg symptoms
• Bladder or bowel dysfunction
• Progressive weakness
• A sensory level

View larger

Plain radiographs come first. They show whether a lesion is lytic (dark, destructive), blastic (white, sclerotic) or mixed, they show deformity, and they give the first estimate of fracture risk. Their weakness is sensitivity: 30-50% of the cortex must be destroyed before a lesion is visible.

View larger

CT assesses the cortex better than the radiograph and quantifies the destruction. CT of the chest, abdomen and pelvis is the staging study, and CT guides biopsy planning.

View larger

MRI is the most sensitive test for marrow involvement and shows soft-tissue extension. It is essential for spinal metastases, and if cord compression is suspected the whole spine is imaged.

View larger

Bone scintigraphy screens the whole skeleton. It is highly sensitive but not specific, and it may miss pure lytic lesions, kidney metastases and myeloma among them. A superscan means widespread metastases.

View larger

View larger

PET-CT is increasingly used for staging. It measures metabolic activity, helps to identify an unknown primary, and monitors the response to treatment.

View larger

View larger

Blood tests.

• Full blood count - anaemia or pancytopenia from marrow infiltration
• Biochemistry - calcium (hypercalcaemia), alkaline phosphatase (raised), LDH
• Tumour markers - PSA (prostate), CEA (gastrointestinal, breast), AFP (germ cell), thyroglobulin
• Serum and urine protein electrophoresis - to exclude myeloma
• Iron studies - a chronic-disease pattern

The unknown primary. When no primary is known the workup is CT of the chest, abdomen and pelvis, PET, tumour markers, and serum and urine electrophoresis. Immunohistochemistry on the biopsy directs where to look next.

Biopsy. Image-guided core needle biopsy is preferred, with the tract aligned to the potential surgical approach, and the tissue goes for histology, immunohistochemistry and molecular studies. Biopsy when:

• The primary is unknown
• The lesion is solitary, since it could be a primary bone tumour
• The presentation is atypical
• There is clinical doubt about the diagnosis

The Mirels score (Mirels, Clin Orthop Relat Res 1989) predicts the risk of pathological fracture in a long-bone metastasis from four parameters, Site, Pain, Lesion and Size (SPLS). Each scores 1 to 3, so the total runs from 4 to 12, and a peritrochanteric location and a lytic lesion score highest.

Reading the total. The reliable half of the score is the bottom of the range:

• 7 or lower - low risk, under 15%: the lesion may be irradiated safely without fixation, with medical management and close observation
• 8 - the grey zone, roughly 15% fracture risk and the original threshold for fixation: weigh the patient's factors, since some may benefit from fixation
• 9 or higher - greater than 33% fracture risk: prophylactic fixation is indicated, with a durable construct that allows weight-bearing

Eight or nine? Mirels described a score of 8 or more as a prelude to fracture, and that is what his paper says. His own fracture rates, 15% at 8 and 33% at 9 or more, underpin the operative threshold of 9 or more that is taught today, with 8 individualised. The score over-predicts fracture, with a specificity of only 35% (Damron 2003), so fixing every 8 overtreats.

Algorithm

View larger

Goals. Treatment is palliative, not curative. The aims are pain relief, function restored or maintained, fracture prevented, quality of life improved, and a durable solution, because the patient may outlive the implant. Nobody delivers that alone: medical oncology, radiation oncology, orthopaedic surgery, palliative care, pain management and physiotherapy all sit in the multidisciplinary team.

What decides the plan.

• The primary tumour type and how responsive it is
• Expected survival
• Performance status
• The extent of metastatic disease
• Fracture risk, by the Mirels score
• The patient's wishes

Skeletal-related events are the major complications of bone metastases that require intervention. Five are counted:

1. Pathological fracture - the most common
2. Spinal cord compression - a neurological emergency
3. Bone pain requiring radiotherapy - severe uncontrolled pain
4. Hypercalcaemia of malignancy - a metabolic emergency
5. Surgery to bone - stabilisation or reconstruction

Pathological fracture occurs in 10-30% of patients with bone metastases. The risk factors: a lytic lesion (higher risk than blastic), a lesion larger than two-thirds of the cortex, a peritrochanteric location, a weight-bearing bone, and a Mirels score of 9 or more. An actual fracture is fixed urgently, with pain controlled, using a durable construct that allows immediate weight-bearing, followed by post-operative radiotherapy; an impending fracture is fixed electively, and the outcomes of prophylactic surgery are better than those of fracture fixation.

Spinal cord compression affects 5-10% of cancer patients. Back pain occurs in 95% and is often the first symptom; motor weakness follows in 75%, sensory change in 50% and bladder or bowel dysfunction in 50%. Hours matter, because neurological recovery correlates with function before treatment. Dexamethasone is given at high dose, 10 mg intravenously then 16 mg daily, with a neurosurgical or spinal consult, and the choice is decompression with stabilisation or radiotherapy; in the Patchell trial in the Evidence Base, decompression followed by radiotherapy kept more patients walking than radiotherapy alone in selected patients with a single area of compression. Prognosis is set by pre-treatment ambulatory status above all, then the time over which the motor deficit developed, the extent of compression and the primary tumour type.

View larger

View larger

Hypercalcaemia of malignancy is a metabolic emergency with three mechanisms: osteoclastic resorption in lytic disease, humoral PTHrP secretion by the tumour, and vitamin D production in lymphoma. It presents with confusion and lethargy, nausea, vomiting and constipation, polyuria and polydipsia, dehydration, and cardiac arrhythmias. Treatment:

• Intravenous hydration, 4-6 L of normal saline
• A bisphosphonate (zoledronic acid)
• Calcitonin, rapid but short-lived
• Denosumab if bisphosphonates fail
• Treat the underlying cancer

Bone pain affects 75% of patients with bone metastases, limits mobility and function, and weighs heavily on quality of life. It comes from periosteal stretching, microfractures, tumour growth, inflammatory mediators and nerve compression. Its management is the medical management already described, with neurolytic procedures for refractory pain.

Surgical complications. Intraoperatively: massive haemorrhage (especially with kidney and thyroid primaries), cement extravasation, neurovascular injury and fat embolism. Postoperatively: wound complications in 15-20%, infection in 5-10% (higher than in non-cancer surgery), implant failure, local tumour progression, and DVT or PE in a high-risk population. The defences are the principles already stated: preoperative embolisation for vascular tumours, meticulous technique, adequate cement, post-operative radiotherapy, DVT prophylaxis and the multidisciplinary team.

Late problems. Radiotherapy impairs fracture healing, causes soft-tissue fibrosis and rarely a radiation-induced fracture. Bone-targeted agents carry a 1-2% risk of osteonecrosis of the jaw, rare atypical femoral fractures, and renal impairment with bisphosphonates. And the disease progresses: local recurrence despite treatment, new skeletal lesions, visceral metastases and a declining performance status.

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.

The solitary metastasis may represent oligometastatic disease and carries a better prognosis than polymetastatic disease. Consider aggressive local treatment; in selected cases that means wide resection with adjuvant therapy.

Renal cell carcinoma is the special case. Beyond embolisation, it may be radiosensitive (modern targeted therapy), tyrosine kinase inhibitors and immunotherapy have improved outcomes, and for a solitary metastasis nephrectomy with metastasectomy is considered.