Metastatic Bone Disease

Metastatic bone disease is the spread of a non-skeletal cancer to bone, and it is the commonest malignant process of the skeleton in adults, far outnumbering primary bone tumours. Up to 70% of patients with advanced breast or prostate cancer develop bone metastases, and the condition is also frequent in lung, kidney, thyroid and myeloma related disease.

Breast, prostate, lung, kidney and thyroid cancers account for about 80% of bone metastases. The axial skeleton is most often involved (vertebrae in 60 to 70%, then pelvis, ribs, skull), followed by the proximal femur and humerus. Lesions are lytic (lung, kidney, thyroid, myeloma), sclerotic (prostate, some breast) or mixed (breast). The peak age is 50 to 70 years.

Skeletal related events are pathological fracture, spinal cord or cauda equina compression, hypercalcaemia of malignancy, and need for radiotherapy or surgery to bone. They cause pain, loss of mobility and independence, and shorten survival. Median survival after diagnosis depends on the primary: years for breast and prostate, months for lung.

Pathophysiology.

Tumour cells reach bone through the vertebral venous plexus and the rich red marrow blood supply. In the "vicious cycle", tumour cells release parathyroid hormone related peptide, interleukin 6 and other factors that raise RANK ligand, which activates osteoclasts. Bone resorption releases growth factors (transforming growth factor beta, insulin like growth factors) that feed tumour growth. In prostate cancer, endothelin 1 and Wnt signalling stimulate osteoblasts to make weak sclerotic bone.

Weakened cortex fails under load, and cord compression follows vertebral collapse or epidural tumour growth.

Progressive bone pain that is worse at night and at rest, and not relieved by position. Mechanical pain on weight bearing signals impending fracture. A sudden severe pain after minor movement is a pathological fracture. Spinal cord compression presents with back pain, band like thoracic pain, limb weakness, sensory loss, a sensory level, urinary retention, and bowel dysfunction; it needs same day action.

Hypercalcaemia causes thirst, polyuria, constipation, nausea, confusion and drowsiness. Bone marrow infiltration causes anaemia and thrombocytopenia (leucoerythroblastic picture).

Examine for a known or occult primary (breast, prostate, thyroid, lung, abdomen), local tenderness, deformity, range, and a full neurological examination including a rectal and perineal assessment when the spine is involved.

• Radiographs of the symptomatic site (a lytic lesion needs 30 to 50% cortical loss before it is visible). Whole length films of long bones.
• MRI of the whole spine for any suspected cord compression, taken within 24 hours, because skip lesions are common. It is the most sensitive test for marrow disease.
• CT chest, abdomen and pelvis (staging and finding an occult primary), CT of the lesion for bone destruction, and Mirels scoring.
• Bone scan, positron emission tomography with CT, or whole body MRI for the extent of disease; bone scan can miss purely lytic lesions (myeloma, renal).
• Blood tests: full blood count, urea, creatinine, calcium (corrected for albumin), phosphate, alkaline phosphatase, liver function, lactate dehydrogenase, prostate specific antigen, protein electrophoresis and serum free light chains, thyroid function.
• Biopsy when the primary is unknown or the diagnosis changes treatment (CT-directed core biopsy before any fixation, with immunohistochemistry), taken by the team that will treat the lesion.
• The Mirels score (site, pain, lesion type, size, each scored 1 to 3) predicts fracture risk in long bones: 9 or more needs prophylactic fixation, 8 is borderline, 7 or less can be observed. The Spinal Instability Neoplastic Score grades spinal stability (13 to 18 unstable).

Differential diagnosis.

• Primary bone tumour (osteosarcoma, chondrosarcoma, lymphoma) and myeloma.
• Osteoporotic or traumatic fracture and osteomyelitis.
• Paget disease and brown tumour.
• Benign lesions (haemangioma, bone cyst, enostosis).

Treatment aims to control pain, keep function, prevent skeletal events, and treat the underlying cancer, in a multidisciplinary team (oncology, radiotherapy, orthopaedics or spinal surgery, palliative care, interventional radiology).

Analgesia.

• Paracetamol 1 g orally every 6 hours (maximum 4 g daily; 3 g daily when weight is under 50 kg, with chronic alcohol use or hepatic impairment).
• Ibuprofen 400 mg orally every 8 hours with food for short courses (maximum 1200 mg daily); avoid with eGFR under 30 mL/min/1.73 m2, peptic ulcer, heart failure, thrombocytopenia or anticoagulant use.
• Oral morphine 5 to 10 mg every 4 hours as needed for severe pain, titrated to effect (start 2.5 to 5 mg with age over 75 or eGFR under 30 mL/min/1.73 m2; no fixed ceiling when titrated under review). Monitor sedation and respiration and prescribe a laxative. Convert to a modified release preparation once the daily need is stable.
• Neuropathic pain: gabapentin 300 mg orally at night, increased by 300 mg every 1 to 3 days to 300 to 600 mg three times daily (maximum 1800 mg daily; reduce at creatinine clearance under 60 mL/min); monitor sedation and dizziness.

Radiotherapy. External beam radiotherapy gives pain relief in 60 to 80% of painful lesions: a single fraction of 8 Gy for uncomplicated painful bone metastases, and 20 Gy in 5 fractions for spinal cord compression (or 30 Gy in 10 fractions) after steroids. Stereotactic body radiotherapy offers higher doses for oligometastatic and radioresistant disease.

Radiotherapy follows fixation of a fracture to treat the rest of the bone (after 2 to 4 weeks). Radium-223 55 kBq/kg intravenously every 4 weeks for 6 cycles is used in castration resistant prostate cancer with symptomatic bone disease and no visceral disease (check blood count before each dose; avoid with bone marrow failure).

Spinal cord compression. Lie flat with spinal precautions until stability is known. Dexamethasone 16 mg orally or intravenously once daily (in one or two doses) with a proton pump inhibitor, started at once when there is a neurological deficit (some give a 10 mg intravenous loading dose). Monitor glucose and mood. Avoid before biopsy when lymphoma is suspected. Taper over 2 weeks after radiotherapy or surgery.

Urgent spinal surgery (decompression and stabilisation) when the spine is unstable, the cause is a fracture fragment, the primary is unknown with a good prognosis, or radiotherapy fails; otherwise radiotherapy.

Bone modifying agents (for lytic or mixed disease, myeloma, breast and prostate cancer).

• Zoledronic acid 4 mg intravenously over at least 15 minutes every 4 weeks for the first year, then every 12 weeks. Reduce the dose to 3.5 mg at creatinine clearance 50 to 60 mL/min, 3.3 mg at 40 to 49 mL/min and 3.0 mg at 30 to 39 mL/min; avoid below 30 mL/min.
• Check creatinine, calcium and phosphate before each dose, and give colecalciferol 800 to 2000 IU daily with calcium 500 mg daily. Avoid with hypocalcaemia and pregnancy.
• Denosumab 120 mg subcutaneously every 4 weeks (can be used in renal impairment). Check calcium before each dose; correct hypocalcaemia first; give colecalciferol 800 to 2000 IU daily with calcium 500 mg daily. Hypocalcaemia is more frequent than with zoledronic acid, and stopping suddenly causes rebound fractures.
• A dental review before either drug. Osteonecrosis of the jaw (1 to 2%) and atypical femoral fractures are risks with prolonged use; avoid invasive dental work during treatment.

Hypercalcaemia of malignancy. Intravenous 0.9% sodium chloride 2 to 4 L over 24 hours to restore volume (watch for fluid overload), then zoledronic acid 4 mg intravenously over 15 minutes once (check creatinine); repeat after 7 days if needed. Denosumab 120 mg subcutaneously for refractory or renally impaired cases. Stop thiazides, calcium and vitamin D supplements.

Systemic cancer treatment. Hormonal, targeted, chemotherapy or immunotherapy by the primary site (for example androgen deprivation in prostate cancer, endocrine therapy in breast cancer), led by oncology.

Orthopaedic surgery.

• Prophylactic fixation of an impending fracture (Mirels 9 or more, or a painful lesion over 50% of the cortex at the femoral neck or subtrochanteric region): intramedullary nail, with cement augmentation if needed.
• Pathological fracture: intramedullary nailing for the femur, tibia and humerus, and endoprosthetic replacement for the femoral head and neck, proximal humerus, and periarticular bone destruction or when the primary is radioresistant (kidney, thyroid).
• Vertebral cement augmentation (vertebroplasty, kyphoplasty), percutaneous fixation, or separation surgery with stereotactic radiotherapy for spinal disease.
• Surgery needs an expected survival over 3 months and fitness for anaesthesia. Preoperative embolisation of vascular tumours (kidney, thyroid) reduces blood loss.
• Radiofrequency, cryoablation and cementoplasty for painful lesions in selected patients.

Operative antibiotic prophylaxis. Cefazolin 2 g intravenously (3 g when weight is 120 kg or over) within 60 minutes before incision as a single dose (repeat after 4 hours or blood loss over 1500 mL). With severe penicillin allergy, vancomycin 15 mg/kg intravenously starting 90 to 120 minutes before incision as a single dose, with levels and creatinine checked in prolonged cases.

Tranexamic acid (major surgery). Tranexamic acid 15 mg/kg (maximum 1 g) intravenously over 10 minutes before incision, repeated once after 3 hours if bleeding continues (maximum 2 g); avoid with a history of thromboembolism, active intravascular clotting, or seizures; reduce the dose at creatinine clearance under 50 mL/min.

Thromboprophylaxis. Cancer and immobility raise the risk. Enoxaparin 40 mg subcutaneously once daily, started 6 to 12 hours after surgery and continued for 28 to 35 days . Reduce to 20 mg once daily at creatinine clearance under 30 mL/min. Adjust by anti-Xa level in obesity and renal impairment. Check the platelet count on days 5 to 14 for heparin induced thrombocytopenia. Use mechanical prophylaxis until then.

Monitoring. Pain, function and neurological state at each visit. Imaging of treated lesions at 3 months and then by the oncology plan. Calcium, creatinine and phosphate before each bone modifying dose. Dental review every 6 months. Bone health (calcium, vitamin D) during hormone therapy.

Referral and escalation. Refer every patient with suspected metastatic bone disease to oncology, and any impending or actual pathological fracture to orthopaedic oncology. Emergency referral the same day for suspected spinal cord compression, a neurological deficit, an unstable spine, hypercalcaemia with confusion, or a displaced pathological fracture.

Special groups.

• Myeloma: bone modifying agents are used as part of treatment, and biopsy and light chain tests should precede surgery.
• Unknown primary: biopsy is needed before fixation; the commonest are lung, kidney and myeloma.
• Renal impairment: choose denosumab, or adjust zoledronic acid; avoid NSAIDs; reduce morphine doses.
• Frail or end of life: palliative radiotherapy, analgesia and cement augmentation; avoid major surgery.